Ocular Pharmacology PDF

Textbook on
Clinical Ocular Pharmacology

and Therapeutics
Textbook on
Clinical Ocular Pharmacology
and Therapeutics
Editors
SK Gupta
PhD DSc FIPS FIACS
Head, Clinical Research
Delhi Institute of Pharmaceutical Sciences and Research (DIPSAR)
University of Delhi
New Delhi, India
Renu Agarwal PhD

Faculty of Medicine
Universiti Teknologi MARA
Selangor, Darul Ehsan, Malaysia
Sushma Srivastava PhD

Department of Pharmacology
Delhi Institute of Pharmaceutical Sciences and Research (DIPSAR)
University of Delhi
New Delhi, India
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Textbook on Clinical Ocular Pharmacology and Therapeutics

First Edition: 2014
ISBN 978-93-5152-341-3
Printed at
Contributors
Anna Krasilnikova PhD Meenakshi Kanwar Chauhan PhD
Faculty of Medicine Department of Pharmaceutics
Universiti Teknologi MARA Delhi Institute of Pharmaceutical Sciences and
Selangor, Darul Ehsan, Malaysia Research (DIPSAR), University of Delhi
New Delhi, India
Azida Juana Wan Abdul Kadir MD
University Malaya Medical Center Miswan Muiz Mahyudin MD
Faculty of Medicine Faculty of Medicine
University of Malaya, Malaysia Universiti Teknologi MARA
Selangor, Darul Ehsan, Malaysia
Binit Kumar PhD
Mustafa Ahmed Jirjees FIBMS
Delhi Institute of Pharmaceutical Sciences and
Faculty of Medicine
Research (DIPSAR), University of Delhi
MAHSA University College
New Delhi, India
Kresge Eye Institute Kuala Lumpur, Malaysia
School of Medicine
Wayne State University Nabanita Halder PhD
MI, USA Department of Ocular Pharmacology
Dr Rajendra Prasad Center for Ophthalmic Sciences
Brandie R Morgan PhD All India Institute of Medical Sciences
Harry S Truman Memorial Veterans’ Hospital New Delhi, India
Columbia, Missouri, USA
Department of Ophthalmology Nafeeza Mohd Ismail PhD
School of Medicine and College of veterinary Medicine Faculty of Medicine
University of Missouri Universiti Teknologi MARA
Columbia, Missouri, USA Selangor, Darul Ehsan, Malaysia
Brinnell Annette Caszo PhD Preeti Sankaran MD

Department of Physiology Dr Rajendra Prasad Center for Ophthalmic Sciences
Faculty of Medicine and Defence Health All India Institute of Medical Sciences
National Defence University New Delhi, India
Kuala Lumpur, Malaysia
Puneet Agarwal MD
Igor N Iezhitsa PhD
Department of Ophthalmology
Faculty of Medicine
IMU Clinical School
Selangor, Darul Ehsan, Malaysia International Medical University
Department of Pharmacology Seremban, Malaysia
Volgograd State Medical University, Russia
Rajani Mathur PhD
Lwin Lwin Nyein MD Department of Pharmacology
Faculty of Medicine Delhi Institute of Pharmaceutical Sciences and
Universiti Teknologi MARA Research (DIPSAR), University of Delhi
Selangor, Darul Ehsan, Malaysia New Delhi, India
vi Textbook on Clinical Ocular Pharmacology and Therapeutics
Rajiv R Mohan PhD Sunil Gurtu MD
Harry S Truman Memorial Veterans’ Hospital Monash University, Sunway Campus
Columbia, Missouri, USA Jeffrey Cheah School of Medicine and
Department of Ophthalmology Health Sciences
School of Medicine and College of veterinary Medicine Selangor, Darul Ehsan, Malaysia
University of Missouri
Columbia, Missouri, USA Sushil Vasudevan MD
Faculty of Medicine
Renu Agarwal PhD Universiti Teknologi MARA
Faculty of Medicine Selangor, Darul Ehsan, Malaysia
Selangor, Darul Ehsan, Malaysia Sushma Srivastava PhD
Rohit Saxena MD Delhi Institute of Pharmaceutical Sciences and
Department of Ophthalmology Research (DIPSAR), University of Delhi
Dr Rajendra Prasad Center for Ophthalmic Sciences New Delhi, India
All India Institute of Medical Sciences
New Delhi, India T Velpandian PhD
Department of Ocular Pharmacology
SK Gupta PhD DSc FIPS FIACS Dr Rajendra Prasad Center for Ophthalmic Sciences
Head, Clinical Research All India Institute of Medical Sciences
Delhi Institute of Pharmaceutical Sciences and New Delhi, India
Research (DIPSAR), University of Delhi
New Delhi, India Vijay Kumar MPharm
Department of Ocular Pharmacology
Shrikant Gaur BSc BAMS (DU) Dr Rajendra Prasad Center for Ophthalmic Sciences
Head, Medical Research All India Institute of Medical Sciences
Promed Research Center New Delhi, India
Gurgaon, Haryana, India
Vinay Gupta MD
Sujaya Singh MD Department of Ophthalmology
Faculty of Medicine Dr Rajendra Prasad Center for Ophthalmic Sciences
Universiti Teknologi MARA All India Institute of Medical Sciences
Selangor, Darul Ehsan, Malaysia New Delhi, India
Preface
The eye and the drugs used to treat ophthalmic ailments, although have been the attractive areas for
scientific investigations since the ancient time; 21st century has witnessed explosive growth and
development in this field. The students and practitioners are now confronted with the dilemma of how
to consolidate basic concepts of pharmacology and knowledge about the newly developed drugs. This
book aims to provide essential knowledge of the basic concepts of pharmacology, their application
in ocular pharmacology and basic pharmacology of commonly used drugs in ophthalmology.
The book also discusses the possible adverse drug reactions of systemically administered drugs.
The ophthalmologists and postgraduates will find the book very useful in understanding basic
pharmacology concepts, which can be utilized in therapeutics. The contents of the book are formatted
in a way to provide quick to the point and easy access to the relevant matter. We believe that the
subject matter in this book will be very useful for practicing ophthalmologist as a guide to answer
questions that commonly arise during patient care. At the same time students find it useful to prepare
for various board and certificate examinations. Although, this book can be used as quick reference,
it provides enough subject matter to be used as stand-alone text without reference to larger volumes.
Contents of the book have been organized with great caution; however, the feedback from the students
and clinicians would be invaluable in improving the format as well as the contents of the book in
future editions.
We sincerely thank all authors who have contributed immensely in putting the subject matter of
this book in its current form. Without their expertise and time, this book would not be complete.
We shall feel highly rewarded if the objectives of presenting this book are fulfilled and students
and practitioners can use it to their advantage in understanding the subject.
SK Gupta
Renu Agarwal
Sushma Srivastava
Acknowledgments
I acknowledge the financial support from Department of Science and Technology (DST), New
Delhi, for the financial assistance received under USERS project. My sincere thanks to Dr SS Kohli,
Scientist F/Director, SERC division, DST, for his constant support and encouragement.
I thank all the contributors for their outstanding contributions. Despite their busy schedule and
pressing commitments, they have put their best effort to give shape to this textbook.
My special thanks to my colleagues and students at Delhi Institute of Pharmaceutical Sciences
and research, for their valuable help in editorial assistance, without which this task would have
been meaningless.
SK Gupta
DRUGS USED IN OCULAR THERAPEUTICS
AT A GLANCE
Ocular therapeutics in recent years has undergone tremendous changes not only in terms of introduction
of new drugs and new drug classes but also in terms of development of novel drug delivery systems.
This introductory section presents a summary for quick reference to currently used drugs from different
therapeutic classes. The chapters that follow this section will discuss the basic and clinical pharmacology
of each of these drug classes and drugs.
Route of
Drug (generic) Drug class Clinical use Trade name Formulation administr
ation
MYDRIATICS AND CYCLOPLEGICS
Atropine sulfate Anticholinergic Pupillary Atropine-care Solution 1% Topical
dilatation and Isopto atropine Ointment 1%
cycloplegia Generic
Homatropine Anticholinergic Pupillary Isopto Solution 2%, 5% Topical
hydrobromide dilatation and homatropine
cycloplegia Generic
Cyclopentolate Anticholinergic Pupillary Cyclogyl Solution 0.5%, 1%, Topical
hydrochloride dilatation and 2%
cycloplegia AK-Pentolate Solution 1%, 2%
Generic Solution 1%
Tropicamide Anticholinergic Pupillary Tropicacyl Solution 0.5%, 1%, Topical
dilatation and Mydriacyl
cycloplegia
Generic
Scopolamine Anticholinergic Pupillary Isopto hyoscine Solution 0.25% Topical
hydrobromide dilatation and
cycloplegia
Phenylephrine Sympathomimetic Pupillary Mydfrin Solution 2.5% Topical
hydrochloride dilatation Neo-Synephrine Solution 2.5%
AK-Dilate Solution 2.5%, 10%
Generic Solution 2.5%, 10%
Hydroxyamphe- Sympathomimetic/ Pupillary Paremyd Solution Topical
tamine anticholinergic dilatation and 1%/0.25%,
hydrobromide/ cycloplegia
tropicamide
Following combinations are also available in India:
Atropine sulphate 1% w/v, chloramphenicol 0.5%, dexamethasone sodium phosphate 0.1%.
Atropine sulphate 1%, prednisolone 0.25%, chlorobutanol 0.5%.
Atropine sulphate 10 mg, tetracycline 10 mg.
Cyclopentolate 1%, dexamethasone sodium phosphate 0.1%.
Cyclopentolate hydrochloride 1%, phenylephrine hydrochloride 5%.
Phenylephrine hydrochloride 5%, tropicamide 0.8%.
Homatropine hydrobromide 2%, chlorbutol 0.5%.
Tropicamide 0.8%, phenylephrine 5%.
Tropicamide 0.8%, phenylephrine hydrochloride 0.5%.
Tropicamide 0.8% w/v, phenylephrine hydrochloride 5%.
Tropicamide 1%, chlorbutol 0.5%
Contd...
xii Textbook on Clinical Ocular Pharmacology and Therapeutics
Contd...
ANESTHETIC AGENTS
Lidocaine Amide type of local anesthetic Ocular surface Akten Solution 3.5%
hydrochloride anesthesia
Proparacaine Ester type of local anesthetic Ocular surface Alcaine Solution 0.5%
Ocu-caine
Ophthetic
Paracaine
Generic
Tetracaine Ester type of local anesthetic Ocular surface Generic Solution 0.5%
Following injectable anesthetic agents are available for regional anesthesia:
1. Bupivacaine (Amide type): 0.25–0.75%
2. Lidocaine (Amide type): 1–2%/500 mg
3. Mepivacaine: (Amide type): 1–2%/500 mg
4. Prilocaine (Amide type): 1–2%/600 mg
5. Etidocaine (Amide type): 1%
6. Procaine (Ester type): 1–2%/500 mg
7. Tetracaine (Ester type): 0.25%
ANTI-INFLAMMATORY AGENTS
Diclofenac NSAID Ocular inflammation Voltaren Solution 0.1%
sodium
Generic
Flurbiprofen NSAID Ocular inflammation Ocufen Solution 0.03%
sodium
Generic
Bromfenac NSAID Ocular inflammation Bromday Solution 0.09%
Nepafenac NSAID Ocular inflammation Nevanac Solution 0.1%
Ketorolac NSAID Ocular inflammation, seasonal Acular® Solution 0.5%
tromethamine allergic conjunctivitis
Acular LS Solution 0.4%
Acular PF Solution 0.5%
(Preservative
free)
Generic Solution 0.5%
ANTI-HISTAMINICS, DECONGESTANTS, ASTRINGENT
Olopatadine Histamine H1- Seasonal Patanol Solution 0.1% Topical
hydrochloride antagonist, Mast allergic
Pataday Solution 0.2%
cell inhibitor conjunctivitis
Epinastine Histamine H1-, H2- Seasonal Elestat Solution Topical
hydrochloride antagonist, Mast allergic 0.05%
Generic
Azelastin Histamine H1- Seasonal Optivar® Solution Topical
hydrochloride antagonist, Mast allergic 0.05%
Generic
Emedastine Histamine H1- Seasonal Emadine® Solution Topical
difumarate antagonist allergic 0.05%
conjunctivitis
Contd...
Drugs used in ocular therapeutics xiii
Contd...

Alcaftadine Histamine H1- Seasonal allergic Lastacaft Solution 0.25% Topical
antagonist, Mast cell conjunctivitis
inhibitor
Ketotifen fumarate Histamine H1- Seasonal allergic Alaway Solution 0.025% Topical
antagonist, Mast cell conjunctivitis
Zaditor
inhibitor
Generic
Naphazoline Sympathomimetic Seasonal allergic Albalon Solution 0.05% Topical
hydrochloride + + Histamine H1- conjunctivitis + 0.5%
Vasocon-A
antazoline antagonist
phospahte
Naphazoline Sympathomimetic Seasonal allergic Naphcon-A Solution 0.025% Topical
hydrochloride + + Histamine H1- conjunctivitis, + 0.3%
pheniramine antagonist decongestant, Visine-A
maleate astringent Opcon-A
Cromolyn sodium Mast cell inhibitor Seasonal allergic Crolom Solution 4% Topical
conjunctivitis
Generic
Nedocromil Mast cell inhibitor Seasonal allergic Alocril Solution 2% Topical
sodium conjunctivitis
Lodoxamide Mast cell inhibitor Seasonal allergic Alomide Solution 0.1% Topical
tromethamine conjunctivitis
Pemirolast Mast cell inhibitor Seasonal allergic Alamast Solution 0.1% Topical
potassium conjunctivitis
Naphazoline Sympathomimetic Decongestant AK-Con Solution 0.1% Topical
hydrochloride Albalon Solution 0.1%
All clear Solution 0.012%
All clear AR Solution 0.03%
Clear Eyes Solution 0.012%
Generic
Phenylephrine Sympathomimetic Decongestant AK-Nefrin Solution 0.12% Topical
hydrochloride
Generic
Oxymetazoline Sympathomimetic Decongestant Visine LR Solution 0.025% Topical

hydrochloride
Tetrahydrozoline Sympathomimetic Decongestant Murine Tear 0.05% Topical
hydrochloride Drops
Visine
Visine
Advanced
Relief
Generic
Naphazoline Sympathomimetic Decongestant, Clear Eyes 0.0125% Topical

hydrochloride + astringent ACR
zinc sulfate
Contd...
xiv Textbook on Clinical Ocular Pharmacology and Therapeutics
Contd...
Naphazoline Sympathomimetic Decongestant, VIVA Topical
hydrochloride + astringent Lubricating
polysorbate 80 Redness
Relief
Tetrahydrozoline + Sympathomimetic Decongestant, Visine AC 0.05% Topical
zinc sulfate astringent
Following combinations are available in India:
Sodium chloride 0.05%, boric acid 1.25%, chlorpheniramine maleate 0.01%, naphazoline hydrochloride
0.056%, zinc sulfate 0.012%
Diclofenac sodium 1 mg, gentamicin sulfate 3 mg/mL.
Ketorolac tromethamine 4 mg, ofloxacin 3 mg/mL.
Naphazoline 0.15%, methylcellulose 0.2%, chlorpheniramine maleate 0.01%.
Ketorolac 0.5 %, fluorometholone 0.1%.
Triamcinolone acetonide 1 mg, gramicidin 0.25 mg, neomycin sulphate 2.5 mg/g.
Ketorolac trometamol, ofloxacin.
Ketorolac trometamol 0.5%, chlorpheniramine maleate 0.2%, phenylephrine hydrochloride 0.12%.
Phenylephrine hydrochloride 0.12%, naphazoline hydrochloride 0.05%, menthol 0.005%, camphor 0.01%.
STEROIDS
Dexamethasone Glucocorticoid Anti- Ocu-Dex Solution, Ointment Topical
sodium phosphate inflammatory 0.1%, 0.5%
Maxidex Suspension 0.1%,
Ointment 0.1%,
0.5%
Fluorometholone Glucocorticoid Anti- FML SOP Ointment 0.1% Topical
inflammatory Fluor-Op Suspension 0.1%
FML Suspension 0.1%
FML Forte Suspension 0.25%
Generic Suspension 0.1%
Flarex Suspension 0.1%
Loteprednol Glucocorticoid Anti- Lotemax Ointment 0.5% Topical
etabonate inflammatory Suspension 0.5%
Alrex Suspension 0.2%
Prednisolone Glucocorticoid Anti- Ecocnopred Suspension 1% Topical

acetate inflammatory
Omnipred
Generic
Pred Forte
Pred Mild Suspension 0.12%
Prednisolone Glucocorticoid Anti- AK-Pred Solution 1% Topical
sodium phosphate inflammatory
and 1%
Difluprednate Glucocorticoid Anti- Durezol Emulsion 0.05% Topical
inflammatory
Medrysone Glucocorticoid Anti- HMS Suspension 1% Topical
inflammatory
Contd...
Drugs used in ocular therapeutics xv
Contd...
STEROIDS
Rimexolone Glucocorticoid Anti-inflammatory Vexol Suspension Topical

1%
Fluocinolone Glucocorticoid Anti-inflammatory Retisert 0.59 mg Intraocular
acetonide
Ozurdex Glucocorticoid Anti-inflammatory Dexamethasone 0.70 mg Intraocular
Triamcinolone Glucocorticoid Anti-inflammatory Triesence 40 mg/mL Intraocular

acetonide
Trivaris 80 mg/mL
ANTIGLAUCOMA AGENTS
Apraclonidine Sympathomimetic Oculohypotensive Iopidine Solution 0.5%, Topical
hydrochloride 1%
Brimonidine Sympathomimetic Oculohypotensive Alphagan P Solution 0.1%, Topical
tartrate 0.15%
Generic Solution 0.15%,
0.2%
Dipivefrin Sympathomimetic Oculohypotensive Propine Solution 0.1% Topical
hydrochloride Generic
Epinephrine Sympathomimetic Oculohypotensive Generic Solution 0.5%, Topical
hydrochloride 1%, 2%
Betaxolol Beta-blocker Oculohypotensive Betoptic-S Solution 0.25% Topical
hydrochloride Generic Solution 0.5%
Levobunolol Beta-blocker Oculohypotensive Betagan Solution 0.25%, Topical
hydrochloride Generic 0.5%
Carteolol Beta-blocker Oculohypotensive Generic Solution 1% Topical

hydrochloride
Metipranolol Beta-blocker Oculohypotensive OptiPranolol Solution 0.3% Topical
Generic
Timolol Beta-blocker Oculohypotensive Betimol Solution 0.25%, Topical
hemihydrate 0.5%
Timolol Beta-blocker Oculohypotensive Timoptic Solution 0.25%, Topical
maleate 0.5%
Timoptic-XE Gel 0.25%,
0.5%
Generic Solution and
Gel 0.25%,
0.5%
Pilocarpine Cholinomimetic Oculohypotensive Isopto carpine Solution 1%, Topical
hydrochloride 2%, 4%
Pilopine-HS Gel 4%
Generic Solution 0.5%,
1%, 2%, 3%,
4%, 6%
Contd...
xvi Textbook on Clinical Ocular Pharmacology and Therapeutics
Contd...
ANTIGLAUCOMA AGENTS
Carbachol Cholinomimetic Oculohypotensive Isopto Solution 1.5%, Topical
carbachol 3%
Miostat Solution 0.01%
Latanoprost Prostaglandin analog Oculohypotensive Xalatan Solution Topical
Generic 0.005%
Bimatoprost Prostaglandin analog Oculohypotensive Lumigan Solution 0.01%, Topical
0.03%
Travoprost Prostaglandin analog Oculohypotensive Travatan Solution Topical
Travatan-Z 0.004%
Dorzolamide Carbonic anhydrase Oculohypotensive Trusopt Solution 2% Topical
hydrochloride inhibitor Generic
Brinzolamide Carbonic anhydrase Oculohypotensive Azopt Solution 1% Topical
inhibitor
Methazolamide Carbonic anhydrase Oculohypotensive Generic Tablets 25 mg, Oral
inhibitor 50 mg
Acetazolamide Carbonic anhydrase Oculohypotensive Diamox Tablets 125 Oral
inhibitor mg, 250 mg,
Capsules
extended
release 500 mg
Glycerine Hyperosmotic agent Oculohypotensive Osmoglyn Solution 50% Oral
Mannitol Hyperosmotic agent Oculohypotensive Osmitrol Solution 5–20% Intravenous

Urea Hyperosmotic agent Oculohypotensive Ureaphil Powder Intravenous
(4 g) to be
reconstituted to
30% solution
Following combinations are available in India:
Brimonidine tartrate, timolol maleate.
Brimonidine tartrate 2 mg, timolol maleate 5 mg.
Timolol, bimatoprost.
Dorzolamide 2%, timolol 0.5%.
Bimatoprost 0.03%, timolol 0.5%.
Timolol maleate 0.5%, pilocarpine 2%.
Latanoprost 0.005%, timolol maleate 0.5%.
ANTIBACTERIAL AGENTS
Ciprofloxacin Fluoroquinolone Extraocular Ciloxan Solution and Topical
and intraocular Ointment 0.3% Intravenous: 500
infections mg/8 hours
Gatifloxacin Fluoroquinolone Extraocular Zymaxid Solution 0.5% Topical
and intraocular Zymar Solution 0.3%
infections
Levofloxacin Fluoroquinolone Extraocular Iquix Solution 1.5% Topical
and intraocular Quixin Solution 0.5% Intravenous: 500
Moxifloxacin Fluoroquinolone Extraocular Moxeza Solution 0.5% Topical
and intraocular Vigamox Intravenous: 400
Contd...
Drugs used in ocular therapeutics xvii
Contd...
Besifloxacin Fluoroquinolone Extraocular Besivance Solution 0.6% Topical
and intraocular
infections
Ofloxacin Fluoroquinolone Extraocular Ocuflox Solution 0.3% Topical
and intraocular
infections
Sulfacetamide Sulfonamide Extraocular Bleph-10 Solution 10% Topical
infections Sulf-10 Solution 10%
Sulf-10 preserv Ointment 10%
ative free
Gentamicin Aminoglycoside Extraocular Genoptic Solution 0.3% Topical
sulfate and intraocular
infections Subconjunctival:
Genoptic SOP Ointment 0.3% 10–20 mg
Intravitreal:
Gentak Solution 0.3% 100–200 mg
Ointment 0.3% Intravenous: 3–5
mg/kg daily in 2–3
divided doses
Tobramycin Aminoglycoside Extraocular AK-Tob Solution 0.3% Topical
infections Tobrex Solution 0.3%, Subconjunctival:
Ointment 0.3% 10–20 mg
Intravitreal:
Tobrasol Solution 0.3% 100–200 mg
Intravenous: 3–5
mg/kg daily in 2–3
divided doses
Neomycin Aminoglycoside Extraocular Neomycin Solution 0.5% Topical
sulfate and intraocular sulfate
125–250 mg
Amikacin Aminoglycoside Extraocular Amikin Solution 0.3% Topical
25 mg
Intravitreal: 400
mg
Intravenous:
3–15 mg/kg daily
in 2–3 divided
doses
Kanamycin Aminoglycoside Extraocular Kanamycin Solution 0.5% Topical
sulfate and intraocular sulfate
30 mg
Intravitreal: 500 mg
Ampicillin Penicillin Intraocular Topical: 50 mg/mL
sodium infections Subconjunctival: 50–150 mg
Intravitreal: 5 mg
Intravenous: 4–12 g daily in 2–3 divided doses
Contd...
xviii Textbook on Clinical Ocular Pharmacology and Therapeutics
Contd...
Penicillin G Penicillin Intraocular Topical: 100,000 units/mL
infections Subconjunctival: 0.5–1 million units
Intravitreal: 300 units
Intravenous: 12–24 million units daily in 4–6
divided doses
Piperacillin Penicillin Intraocular Topical: 12.5 mg/mL
infections Subconjunctival: 100 mg
Ticarcillin disodium Penicillin Intraocular Topical: 6 mg/mL
Cefazolin sodium Cephalosporin Intraocular Topical: 50 mg/mL
Intravenous: 2–4 g daily in 3–4 divided doses
Ceftazidime Cephalosporin Intraocular Topical: 50 mg/mL
Intravenous: 1 g daily in 2–3 divided doses
Ceftriaxone Cephalosporin Intraocular Topical: 50 mg/ml
infections Intravenous: 1–4 g daily in 1–2 divided doses
Erythromycin Macrolide Extraocular Topical: Ointment 0.5%, solution 50 mg/mL
and intraocular Subconjunctival: 100 mg
infections Intravitreal: 500 mg
Azithromycin Macrolide Extraocular Azasite Topical solution 1%
and intraocular Intravenous: 500 mg
infections
Clarithromycin Macrolide Extraocular Topical: 10 mg/mL
and intraocular
infections
Bacitracin zinc Bacitracin Extraocular Topical: 10,000 units/mL, Ointment 500 units/g
and intraocular Subconjunctival: 5000 units
infections
Polymyxin B Polymyxin Extraocular Topical: 10,000 units/mL, Subconjunctival: 10,000
sulfate and intraocular units
infections
Vancomycin Glycopeptide Extraocular Topical: 12.5–25 mg/mL
hydrochloride and intraocular Subconjunctival: 25 mg
infections Intravitreal: 1000 mg
Intravenous: 15–30 mg/kg daily in 1–2 divided doses
Imipenem/ Carbapenem Extraocular Topical: 5 mg/mL
Cilastatin sodium and intraocular Intravenous: 2 g daily in 3–4 divided doses
infections
Combinations of antibacterial agents
Combination Trade name Formulation
Bacitracin/hydrocortisone/neomycin/ Generic Suspension,Ointment: 400 units—1%

polymyxin
Polymyxin B/bacitracin Zinc AK-Poly-Bac Ointment: 10,000–500 units/g
Generic
Contd...
Drugs used in ocular therapeutics xix
Contd...
Polymyxin B/neomycin/bacitracin Neosporin Solution: 10,000 units—1.75–0.025 mg/mL
Generic Ointment: 10,000 units—3.5 mg–400 units/g
Polymyxin B/neomycin/gramicidin Neosporin Solution: 10,000 units—1.75–0.025 mg/mL
Generic Ointment: 10,000 units—3.5 mg–400 units/g
Polymyxin B/trimethoprim Polytrim Solution: 10,000 units—1 mg/mL
Generic
Dexamethasone/neomycin/ Poly-Dex Suspension and ointment: 0.1%—3.5 mg/mL–
polymyxin B 10,000 units/mL
Maxitrol Suspension and ointment: 0.1%—3.5 mg/mL–
10,000 units/mL
Dexasporin Suspension: 0.1%—3.5 mg/mL–10,000 units/mL
AK- Trol Ointment: 0.1%—3.5 mg/mL–10,000 units/mL
Dexamethasone/tobramycin Tobradex Suspension and ointment: 0.1–0.3%
Generic
Fluoromethalone-sulfacetamide FML-S Suspension: 0.1–10%
Gentamicin–prednisolone acetate Pred-G Suspension: 0.3–1.0%
Pred-G SOP Ointment: 0.3–0.6%
Loteprednol etabonate–tobramycin Zylet Suspension: 0.5–0.3%
Prednisolone acetate – Neomycin – Poly-Pred Suspension: 0.5–0.35%–10,000 units/mL
Polymyxin B Generic
Prednisolone acetate – Blephamide Suspension: 0.2–10%
Sulfacetamide Blephamide SOP Ointment: 0.2–10%
Prednisolone sodium phosphate – Vasocidin Solution: 0.23–10%
Sulfacetamide Generic
Following combinations are also available in India:
Moxifloxacin hydrochloride 5 mg, dexamethasone phosphate 1 mg.
Chloramphenicol 5%, beclometasone dipropionate 0.025%, clotrimazole 1%, lignocaine hydrochloride 2%.
Bacitracin 500 u and polymyxin B sulfate 10,000 u.
Trimethoprim 1 mg, polymyxin B sulfate 10000 IU, polyvinyl alcohol 0.25%.
Ciprofloxacin 0.3%, dexamethasone 0.01%.
Chloramphenicol 0.2%, prednisolone acetate 0.5%.
Chloramphenicol 0.5%, dexamethasone sodium phosphate 0.1%.
Chloramphenicol 0.5 % dexamethasone 0.01 %.
Chloramphenicol 0.5%, atropine 1%, dexamethasone 0.01%,.
Neomycin 0.5%, dexamethasone 0.01%.
Neomycin sulfate 0.5%, dexamethasone sodium phosphate 0.1%.
Moxifloxacin hydrochloride 0.5%, ketorolac 0.5%
Gatifloxacin 0.3%, dexamethasone 0.1%.
Polymyxin B 5000 IU, chloramphenicol 10 mg, betamethasone 1 mg.
Ofloxacin 0.3%, prednisolone acetate 1%, benzalkonium chloride 0.05%.
Polymyxin B sulfate 5000 IU, chloramphenicol 10 mg.
Ofloxacin 0.3%, betamethasone 0.01%.
Ofloxacin 0.3%, dexamethasone 0.01%.
Chloramphenicol 0.5%, flurbiprofen sodium 0.03%.
Gatifloxacin 0.3%, dexamethasone 0.01%.
Gatifloxacin 0.3%, prednisolone acetate 1%.
Gentamycin 0.3%, dexamethasone 0.01%.
Gentamycin sulfate 0.3%, hydrocortisone acetate 1%.
Gentamicin sulfate 0.3%, betamethasone sodium phosphate 0.1%
Ofloxacin 0.3%, dexamethasone 0.1%.
Ketorolac tromethamine 5 mg, ofloxacin 3 mg/1 mL.
Tobramycin sulfate 0.3%, fluorometholone 1%.
Contd...
xx Textbook on Clinical Ocular Pharmacology and Therapeutics
Contd...
ANTIFUNGAL AGENTS
Amphotericin B Topical: 0.1–0.5% solution
Subconjunctival: 0.8–1.0 mg
Ambisome Intravitreal: 5 mg
(intravenous) Intravenous: 3–5 mg/kg/day
Natamycin Natacyn Topical: 5% suspension
Fluconazole Diflucan Oral: 150 mg single dose; 200 mg on day 1

followed by 100 mg daily; 400 mg on day 1
followed by 200 mg daily.
Intravenous: 100–400 mg daily

Itraconazole Sporanox Oral: 200–400 mg daily
Intravenous: 200 mg twice a day for 2 days
followed by 200 mg daily for 14 days
Voriconazole Vfend Topical: 1% solution prepared from IV formulation.
Oral: 200 mg twice a day
Intravenous: 3–6 mg/kg every 12 hours
Clotrimazole Oral: One troche 5 times a day
Ketoconazole Nizrol Oral: 200–400 mg/day
Posaconazole Noxafil Oral: 200 mg thrice daily; 100 mg twice on day 1
followed by 100 mg/day for 13 days; 400 mg twice
a day
Anidulafungin Eraxis Intravenous: 100 mg/day
Caspofungin Cancidas Intravenous: 50 mg/day
Mycafungin Mycamine Intravenous: 100 mg/day
Flucytosine Ancobon Oral: 50–150 mg/kg daily in 4 divided doses
Griseofulvin Oral: 500 mg/day
Oral (Ultramicrosize): 375–750 mg/day
Terbinafine Lamisil Oral: 250 mg/day
ANTIVIRAL AGENTS
Acyclovir sodium Zovirax Herpes simplex keratitis (Acute infection): oral:
Generic 400 mg 5 times/day for 1–2 weeks
Herpes simplex keratitis (prophylaxis): oral: 400
mg twice/day
Herpes zoster ophthalmicus: Oral: 800 mg 5 times/
day for 7–10 days
Famcyclovir Famvir Herpes zoster ophthalmicus: Oral: 500 mg 3 times/
day for 7 days
Gencyclovir sodium Zirgan Herpes dendritis keratitis: Topical 0.15% gel, 5
times/day until the ulcer heals followed by 3 times
a day for 7 days
Cytovene Intravitreal: 200 mg
Intravenous: Induction—5 mg/kg administered
over 1 hours, every 12 hours for 2–3 weeks;
Maintenance: 5 mg/kg/day for 7 days/week or 6
mg/kg/day for 5 days/week
Vitrasert Intravitreal insert: 4.5 mg-releases drug over 5–8
months
Contd...
Drugs used in ocular therapeutics xxi
Contd...
ANTIVIRAL AGENTS
Valacyclovir Valtrex Herpes zoster ophthalmicus: Oral: 1 g thrice/day
for 7 days
Valganciclovir valcyte CMV retinitis: Oral: Induction: 900 mg/12 hours for
21 days.
Maintenance: 900 mg/day
Cidofovir Vistide Intravenous: Induction—5 mg/kg administered
over 1 hours once a week for 2 weeks.
Maintenance: 5 mg/kg infusion over 1 hours once
every 2 weeks
Foscarnate sodium Foscavir Intravenous: Induction—60 mg/kg (adjusted to
renal function) over 1 hour/8 hours for 2–3 weeks.
Maintenance: 90–120 mg/kg over 2 hours once
daily
OFF-LABEL DRUGS USED IN OPHTHALMOLOGY
DRUGS COMMON USES ACTION and DOSE
Acetylcysteine Used in corneal Acts by inhibiting collagenase, which delays the corneal
conditions like healing
burns, filamentary
keratitis, Dose: Hourly in acute cases, up to 4 times/day for
keratoconjunctivitis maintenance
sicca, corneal melts
Alteplase (tissue Intraocular injection Acts as a thrombolytic agent. There is significant risk of
plasminogen in postvitrectomy hyphema formation
activator) patients to treat
fibrin formation,
to remove fibrin Dose: 3–6 mg postvitrectomy, 6–12 mg to remove fibrin
membranes membranes
occluding
intraocular portions
of shunts
5-Fluorouracil Post-glaucoma It is an antimetabolite acts by inhibiting fibroblast proliferation.
filtering surgery Associated with risk of conjunctival wound leak, corneal
(indicated in epithelial defects, keratitis, hypotony, reduced visual acuity
patients with high
risk of surgical Dose: Postoperative: Subconjunctival 5 g twice/day for 7 days
failure) followed by once daily for 7 more days
Intraoperative: 50 mg/mL solution soaked in murocell sponge
for 3–5 minutes
Mitomycin C Same as Its action and complications are same as 5-Fluorouracil
5-Fluorouracil
Dose: Intraoperative: Applied once 0.02–0.04% on a small
Additionally has piece of Gelfilm or Weck cell sponge
ben used to prevent
recurrence after
pterygium surgery
and to reduced
scarring after
corneal surgery
such as excimer
laser
Contd...
xxii Textbook on Clinical Ocular Pharmacology and Therapeutics
Contd...
OFF-LABEL DRUGS USE IN OPHTHALMOLOGY
Bevacizumab Used in age- Humanized monoclonal antibody. Acts by inhibiting vascular
(Avastin) related macular endothelial growth factor-A
degeneration,
macular edema
due to retinal Dose: 1.25 mg intravitreal
vein occlusion
or diabetic
retinopathy.
Also used as
surgical adjunct
in procedures
for treatment
of neovascular
glaucoma
Cyclosporin Used to prevent Acts as an immunosuppressant with high selectivity of
(Sandimmune) transplant rejection T lymphocytes
after keratoplasty
Also used to treat

severe vernal Dose: 0.5–2% topical
conjunctivitis,
ligneous
conjunctivitis and
noninfectious
peripheral
ulcerative keratitis
associated
with systemic
autoimmune
disorders
Doxycycline and Used to treat Tetracyclines act by inhibiting bacterial protein synthesis
Minocycline ocular rosacea
meibomianitis and Dose: 100 mg 1–2 times per day for 2–12 weeks
some conditions
involving corneal
melting.
Source: PDR for Ophthalmic Medicines; 40th Edition, 2012; MIMS, India.
Contents
1. Anatomical and Physiological 6. Mydriatics and Cycloplegics 87
Basis of Ocular Pharmacotherapy 1 SK Gupta
Brinnell Annette Caszo Mechanism of Action 87
Eyelids 1 Uses: Diagnostic and Therapeutic 88
Nasolacrimal Apparatus and the Tear Film 3 Commonly Used Mydriatics and Cycloplegics 88
The Bony Orbit 4
Contents of the Bony Orbit 9 7. Ophthalmic Dyes 96
The Visual Pathway 17 SK Gupta, Nabanita Halder
Pupillary Light Reflex 18
8. Antibacterial Agents 102
2. Routes of Ocular Drug Nafeeza Mohd Ismail, Anna Krasilnikova
Administration 21 Beta Lactam Antibiotics 103
Renu Agarwal Penicillins 106
Cephalosporins 109
3. Ocular Pharmacokinetics 28 Carbapenems 111
Renu Agarwal Monobactams 112
Drug Biotransport 28 Oxacephems 112
Passive Diffusion 28 Non-beta Lactam Antibiotics 112
Drug Absorption 30 Quinolones and Fluoroquinolones 115
Bioavailability 38 Tetracyclines 120
Ocular Drug Distribution 39 Macrolides 122
Ocular Drug Elimination 41 Aminoglycosides 125
Multiple Dose Administration and Dosing Sulfonamides 128
Schedule 46 Bacitracin 130
Rational Fixed Dose Combinations 47 Polymyxin B 131
Gramicidin 132
4. Pharmacodynamics 50
T Velpandian, SK Gupta 9. Antiviral Drugs 135
Receptor-mediated Mechanisms of SK Gupta, Rajani Mathur
Drug Action 50 Idoxuridine (Idu) 137
Nonreceptor-mediated Mechanisms of
Trifluridine 137
Drug Action 55
Vidarabine 138
Measurement of Drug Effects 56
Valacyclovir and Acyclovir 139
Measurement of Drug Safety 58
Factors Affecting Drug Responses 58 Famciclovir and Penciclovir 140
Modified Drug Responses 59 Ganciclovir and Valganciclovir 141
Outcomes of Multiple Drug Therapy 62 Cidofovir 142
Adverse Drug Reactions 63 Foscarnet 143
5. Ophthalmic Formulations and 10. Antifungal Drugs 146

Ocular Drug Delivery 65 Nafeeza Mohd Ismail, Anna Krasilnikova
Meenakshi Kanwar Chauhan, Renu Agarwal Polyenes 146
Excipients in Ophthalmic Preparations 65 Pyrimidines 148
Ophthalmic Drug Delivery Systems 72 Azoles 149
Posterior Segment Drug Delivery Systems 82 Echinocandins 152
Modes of Administration of Topical Ophthalmic Griseofulvin 152
Formulations 84 Allylamines 153
xxiv Textbook on Clinical Ocular Pharmacology and Therapeutics
11. Drugs Used in Ocular 18. Drugs Used in the Treatment of

Pain and Inflammation 156 Dry Eyes 240
Sunil Gurtu Miswan Muiz Mahyudin,
Mechanisms of Pain 156 Azida Juana Wan Abdul Kadir
Opioid (Narcotic) Analgesics 157 Aqueous Enhancement Therapy 240
Non-steroidal Anti-inflammatory Drugs Anti-inflammatory Therapy 243
(Nsaids; Non-narcotic Analgesics) 163 Secretagogues 244
Hormonal Therapy 244
12. Corticosteroids 171 Omega-3 Fatty Acids 245
Igor N Iezhitsa
19. Miscellaneous Drugs 246
History 171
Vinay Gupta, Preeti Sankaran,
Pharmacology of Corticosteroids 172
Adverse Effects 176
Sujaya Singh, Sushil Vasudevan,
Puneet Agarwal, Lwin Lwin Nyein,
13. Drugs used in Ocular Allergy 182 Sushma Srivastava, Igor N Iezhitsa,
Sunil Gurtu Shrikant Gaur
Histamine 182 A. Hyperosmotic Agents 246
Antiallergic Drugs 184 Vinay Gupta, Preeti Sankaran,
Ocular Decongestants 190 Sujaya Singh, Sushil Vasudevan
Future Directions 192
Systemic Hyperosmotic Agents 246
14. Local Anesthetics in Pharmacology of Systemic Hyperosmotic
Ophthalmology Practice 194 Agents 246
Topical Hyperosmotic Agents 250
Mustafa Ahmed Jirjees, Puneet Agarwal
B. Surgical Adjuncts 252
Pharmacology of Local Anesthetic Agents 194
Puneet Agarwal
Types of Local Anesthesia 200
Future of Local Anesthetics in Ophthalmic Intraocular Irrigating Solutions 252
Surgery 201 Extraocular Irrigating Solutions 253
Viscoelastic Agents 254
15. Immunomodulators 204 Surgical Miotics 256
Rajani Mathur Surgical Enzymes 256
Botulinum Toxin 256
Ocular Allergies 204
Trypan Blue 256
Cyclosporine 205
Growth Factors 256
Interferons 208 Mitomycin C 257
16. Antiglaucoma Drugs 210 C. Sterilization, Disinfection and Antiseptics
Sushma Sirvastava in Ophthalmology 258
Cholinomimetic Drugs 210 Lwin Lwin Nyein
Sympathomimetics and Sympathetic Definitions 258
Blockers 214 Methods of Sterilization 258
Carbonic Anhydrase Inhibitors 220 Methods of Preventing Contamination in
Prostaglandin Analogs 223 Outpatient Services 261
Systemic Hyperosmotic Agents 224 Preventive Methods in the Operation
Recent Advances in Pharmacotherapy of Theater 262
Glaucoma 224 Prevention in High-risk Areas/Staff 262
Sterilization in Ophthalmic Practice:
17. Drugs used in Retinal Diseases 229 Current Status 263
Rohit Saxena, Binit Kumar D. Contact Lens Care Systems 265
Diabetic Retinopathy 229 Puneet Agarwal
Age-related Macular Degeneration 234 Cleaning Systems 265
Retinal Vein Occlusion 235 Disinfection Systems 266
Contents xxv
Rewetting Solutions 269 Ocular Adverse Effects of Drugs Acting on
Saline Solutions 269 Central Nervous System 305
The Lens Storage Case 269 Ocular Adverse Effects of Drugs Acting on
E. Nutritional Supplements 271 Cardiovascular System 309
Sushma Srivastava, Igor N Iezhitsa, Ocular Adverse Effects of Lipid
Shrikant Gaur Lowering Agents 310
Minerals and Trace Elements 271 Ocular Adverse Effects of Anti-hyperglycemic
Vitamins 273 Agents 311
Amino Acids 279 Ocular Adverse Effects of Therapeutic
Hormones 311
20. Gene Delivery and Disease Ocular Adverse Effects of Analgesic and
Modulation in the Eye 286 Anti-inflammatory Agents 312
Rajiv R Mohan, Brandie R Morgan Ocular Adverse Effects of Antihistamines 313
Conventional Ocular Delivery Ocular Adverse Effect of Antiulcer Drugs 313
Methods and Barriers 286 Ocular Adverse Effects of Antimicrobial Agents 313
Types of Gene Therapy Vectors 287 Ocular Adverse Effects of Anticancer Agents 313
Gene Therapy Applications in Ocular Adverse Effects of Drugs used in
Ophthalmology 292 Dermatological Disorders 315
Nanoparticle Pharmacokinetics: Considerations
Ocular Adverse Effects of Anticoagulants 315
for Gene Therapy Development and
Ocular Adverse Effects of Vitamins 315
Clinical Use 296
Ocular Adverse Effects of other Medications 316
21. Ocular Adverse Effects of
Systemically Administered Drugs 304 Index 321
Vijay Kumar, T Velpandian, Rohit Saxena
Ocular Adverse Effects of Drugs Acting on
Autonomic Nervous System 304
ChapteR 1
Anatomical and Physiological Basis of
Ocular Pharmacotherapy
overview
The principles of therapeutics in the treatment
of ophthalmic diseases require a comprehensive
knowledge of ocular anatomy and physiology.
The understanding of drug interactions at
molecular, cellular and tissue level leading
to pharmacological responses require special
consideration due to the unique anatomical
and physiological characteristics of eye. This Figure 1.1 The eye
chapter provides a basic account of the ocular
anatomy and physiology as a basis of ocular upper and lower lids. The plate is attached to
pharmacotherapy. the orbital septum, which is a thin membranous
The eye and orbit contain smooth and striated sheet attached to the rim and continuous with the
muscle, epithelial tissues, blood vessels, nerves periosteum of the bony orbit.
both autonomic and sensorimotor, connective The layers of the upper eyelid from the facial
tissues and the neuronal tissue, i.e. retina. They aspect inwards include—skin, subcutaneous
are arranged in order to provide an optimum path connective tissue, orbicularis oculi, connective
for the transmittance of light to the light sensitive tissue, tarsal plate, meibomian glands, connective
cells of the retina. Supporting tissues aid and tissue and conjunctiva. Meibomian glands are the
enable this function, and also provide nutrition, tarsal glands that open at the lid margins behind
blood supply and an excretory pathway. the mucocutaneous junction. The tarsal plate also
receives the insertion of the levator palpebrae
muscle. The layers of the lower eyelid consist of
EYELIDS skin, orbicularis oculi muscle, connective tissue,
orbital septum and fat, retractors of the lower eyelid
Structure
and palpebral conjunctiva.1 The retractors of the
The eyelids or palpebrae cover the anterior surface lower eyelid are extensions of the fascia covering
of the eye protecting it from injury and exposure. the inferior oblique muscle and passing forward
The space between the upper and lower lids is called to be inserted into the tarsal plate of the lower lid.
the palpebral fissure, the angle between the lids are It may be referred to as the inferior tarsal muscle
called the medial and lateral canthi (Fig. 1.1). though it has not been completely characterized yet.
The tarsal plate is the main supporting Meibomian glands secrete lipids, mainly
structure of the lids and is present in both the wax and steryl ester that are hydrophobic.
2 Textbook on Clinical Ocular Pharmacology and Therapeutics
They contribute to the layers of the tear film and oculomotor nerve. Thus lesions affecting the
its stability. They are expressed from the gland nucleus often affect both eyelids.3
during blinking.
EFFECT OF DRUGS ON PALPEBRAL FISSURE
MEIBOMIAN GLAND DYSFUNCTION Cholinomimetic drugs with nicotinic action affect the
Meibomian gland dysfunction is a common cause skeletal muscle fibers of levator palpebrae superioris
of eye discomfort especially among users of Video and may cause lid twitching. Adrenergic drugs cause
Display Terminals. Blockage of meibomian contraction of Muller’s muscle leading to widening
gland ducts is quite common and may affect a single of palpebral fissure. Adrenergic blockers such as
or multiple glands. guanethidine cause Muller’s muscle paralysis and
ptosis.
Blood Supply, Lymphatic Drainage Eyelid movements occur in coordination with

and Sensory Nerve Supply of Eyelids the movements of the globe in a way that on
upward gaze vision may not be disturbed and on
Anastomoses of the medial and lateral palpebral downward gaze the eyeball is protected. It appears
arteries supply the eyelids. Venous drainage that the interstitial nucleus of Cajal and the rostral
is into the facial veins or to the ophthalmic interstitial nucleus of the medial longitudinal
veins. Lymphatics drain into the submandibular, fasciculus are the main centers for coordinating
superficial and deep parotid lymph nodes. Sensory eyelid and eye movement.3
innervation is by the ophthalmic and maxillary
divisions of the trigeminal nerves. DISORDERS OF EYELID POSITION
Ptosis is drooping of the upper eyelid. It may be
bilateral due to midbrain lesions involving the 3rd
Motor Nerve Supply and nerve nucleus. When sympathetic fibers supplying
Movements of the Eyelids Muller’s muscle are affected, a slight depression
of the upper eyelid may be present (Horners
Movements of the eyelids are brought about by syndrome). Unilateral ptosis may occur with a 3rd
2 muscles, the orbicularis oculi, for closure of nerve palsy, or a large hemispheric lesion, which
may affect the corticobulbar fibers.
the lids and the levator palpebrae superioris for Blepharospasm is an involuntary spasm of the
opening of the eyelids. Firm closure of the eyelid orbicularis occuli muscle as well as the levator
is achieved by the action of the orbicularis oculi muscle. It is characterized by frequent prolonged
muscle, supplied by the facial nerve. Closure of blinks and the eyelids are pulled below the superior
orbital margins. It may occur in association with
the eyelid for example in the instance of a blink hemifacial spasm caused by irritation of the 7th
occurs by inhibition of the levator palpebrae cranial nerve roots and also along with lesions of
superioris muscle, supplied by the oculomotor the thalamus and brainstem. Blepharocolysis is
nerve and the elastic recoil of the supporting characterized by drooping eyes due to an involuntary
inhibition of the levator palpebrae superioris and
connective tissues. 3 The levator palpebrae no active contribution from the orbicularis muscle.
superioris is responsible for the opening of the It is often associated with Parkinson’s disease,
eyelid. Maximal eyelid opening is achieved by putamenal and subthalamic lesions.3
the added action of the frontalis muscle. Muller’s
muscle or the superior tarsal muscle arises from
the distal part of the levator palpebrae superioris
Conjunctiva
and inserts into the upper margin of the tarsus.3 Mucous membranes that cover the sclera up to the
It is composed of smooth muscle fibers and limbus and the palpebral portions of the eyelids
connective tissue. It is supplied by sympathetic are called conjunctiva. Their main function is
nerves. It is mainly responsible for the width of protection of the anterior surface of the eye
the palpebral fissure. The motor supply is through by secreting the mucous layer of the tear film,
the oculomotor nerve, while the motor neurons antibacterial and antiviral substances and providing
arise from a single central caudal nucleus of the immune defense. The three main regions of the
Anatomical and physiological basis of ocular pharmacotherapy 3
conjunctiva include the palpebral portions covering located in the upper eyelid and the fornices and
the inner side of the eyelids, fornicial conjunctiva probably account for lacrimal secretions after
located at the fornices and the bulbar conjunctiva removal of the lacrimal gland. Accessory glands
covering the white of the eyeball up to the limbus. of Krause are located in the superior and inferior
fornix, while accessory glands of Wolfring are
DEGENERATIVE DISEASES OF CONJUNCTIVA located on the margin of the superior tarsal
Degenerative conditions of the conjunctiva are plate of the upper eyelid.5 The lacrimal gland is
commonly seen with aging. They have minimal effect supplied by the lacrimal branch of the ophthalmic
on vision and are seen frequently, and correlate artery and drains into the superior ophthalmic
with light exposure. Pinguecula is a thickening of
the conjunctiva near limbus in the palpebral fissure vein. It is supplied by parasympathetic fibers
characterized by elastotic degeneration, hyalinization from the pterygopalatine ganglion, which are
and granular deposits. Pterygium is a fibrovascular secretomotor to the gland. Acini of the gland are
growth arising from the conjunctiva and spreading surrounded by myoepithelial cells, which contract
onto the cornea. It occurs more frequently on the
nasal aspect of the palpebral conjunctiva. They to help glandular secretions exit the acini and
may require to be treated as they encroach onto the ductules.
transparent cornea and affect the field of vision. Tears produced by the lacrimal gland bathe
the eye and drain through to lacrimal canaliculi
The conjunctival epithelium, which is non- (Fig. 1.2). The canaliculi are located in the medial
keratinized squamous epithelium contains goblet portion of each eyelid near the medial canthus.
cells secreting mucous and has been shown to be Each canaliculus begins as a punctum in the
capable of phagocytosis.4 Below this layer lies the lacrimal papilla and drains into the lacrimal sac,
conjunctival substantia propria. It is composed of which has a closed upper end and in turn drains
loose connective tissue and is highly vascularized, into the nasolacrimal duct. The duct opens into
and contains a large number of white blood cells. inferior meatus of the nasal cavity. Secretions
from the tarsal meibomian glands also contribute
TRANSCONJUNCTIVAL DRUG ABSORPTION
to the tear film by preventing the rapid evaporation
The cells in the superficial layer of conjunctival
of the fluid (Fig. 1.3).
epithelium have tight junctions similar to cornea and
form a barrier to drug absorption by transconjunctival
route. However, the intercellular spaces in conjunctiva Tear Film
are larger than those in cornea and therefore hydrophilic
drugs are absorbed better through conjunctiva as The tear film is composed of three layers (Fig.
compared to cornea. Due to high vascularity conjunctiva 1.4). The outermost layer consists of lipids from
is also a site for systemic absorption of topically applied
drugs.
the secretions of tarsal glands. It floats on a
middle aqueous layer, contributed by the main
and accessory lacrimal glands. An inner mucous
NASOLACRIMAL APPARATUS AND
THE TEAR FILM
Structure
The lacrimal gland and accessory lacrimal glands
are the main tear-producing structures. The
lacrimal gland consists of an orbital part located
within the orbital margin in the lacrimal fossa of
the zygomatic process of the frontal bone. The
palpebral part is located below the palpebral
conjunctiva. Numerous accessory glands are Figure 1.2 Nasolacrimal apparatus
Figure 1.3 Glands secreting the tear film
layer secreted by goblet cells is in contact with DRY EYES AND EFFECT OF DRUGS ON TEAR
the surface of the conjunctiva and cornea. The SECRETION
mucous layer is hydrophilic and traps particulate Osmolarity of the tear film is one of its most
matter. The aqueous layer makes up more than important properties. Increased osmolarity due to
97% of the volume of secretions, and contains low rate of secretion or increased evaporation leads
most of the proteins, immunoglobulins, lactoferrin to inflammation of the cornea and conjunctiva and
a further reduction in the rate of tear film secretion.
and enzymes. Over a prolonged period of time the surface of the
cornea and conjunctiva may be damaged by these
THE EFFECT OF RATE OF TEAR FLOW ON DRUG
changes.6
ABSORPTION The drugs can affect the quality as well as
The flow of tears normally is about 0.5–2.2 µL/min. quantity of tear secretion. Cholinomimetics stimulate
Ocular irritation results in increased secretion. An the lacrimal gland and increase secretion of both
increased rate of tear flow will dilute drug concentrations the aqueous and mucous components of tears.
and result in lower rates of absorption. Absorption may Antimuscarinic agents produce the opposite
be increased by reducing drainage of tears from the effect and reduce the tear secretion. Sympathetic
eye. Blocking the nasolacrimal duct or tilting the head stimulation causes vasoconstriction leading to
back may increase time for drug absorption through viscous secretion.
the cornea.
THE BONY ORBIT

The orbit or the “sockets” of the eye are bony
cavities that protect the eye and its supporting
structures. The orbit also serves as a passage
to connect the eye with its blood supply and
nerves and also conduct the vessels and nerves
that supply other parts of the face. The bony
boundaries of the orbit are described below. It is
a crowded space filled with numerous vessels,
nerves, connective tissue and muscles apart from
the eyeball. Anesthetic agents are administered
Figure 1.4 Tear film into this space by the retro- and peribulbar route.
Orbital Margins Table 1.1 Dimensions of the orbit7
Superiorly, the orbital margin is formed by the Depth 50–70 mm

orbital arch of the frontal bone. Laterally, it is Volume 30 mL
formed by the zygomatic bone and the zygomatic
Volume of extraocular 7 mL
process of the frontal bone. The zygomatic bone muscles and eyeball
and the maxilla form the inferior border of the
orbital margin. It is slightly raised above the floor
of the orbit. Medially, it is formed by the maxilla
Wall of the Orbit
and lacrimal bone.
The orbit has a superior, medial and lateral wall
EYEBALL INJURIES
and a floor composed of a number of different
The orbital margins are not easily damaged but bones. They are briefly summarized in the
may fracture due to severe injury. Frequently, the
medial margins along with the nose are affected.
Figures 1.5 to 1.7 and Table 1.2.9
The trochlea may be damaged or displaced leading The superior wall is concave anteriorly, where
to symptoms consistent with the paralysis of the the maximum diameter of the orbit is about 1.5 cm
superior oblique. Zygoma fractures may involve the from the orbital margin and more or less flattened
lateral margins and also the lower margin of the orbit.
The orbital margin in general provides better
posteriorly. It contains the fossa for the lacrimal
protection when large objects strike the eye. Smaller gland in the anterolateral aspect of the frontal
objects such as a golf ball for example may strike bone. The trochlear fossa lies anteromedially, and
the eye. The eyeball is most vulnerable to traumatic contains the trochlea through which the tendon of
rupture when struck by a blow directed lateral to
medial and upwards.
the superior oblique passes. Anteriorly it is related
to the air sinuses of the frontal bone. It separates
The outer limits of the orbit are formed the orbit from the anterior cranial fossa and the
by bony boundaries. They form a roughly frontal lobes of the brain.
quadrilateral pyramidal shape and accommodate The medial wall contains the lacrimal fossa
the globe of the eye, the extra-ocular muscles for the lacrimal sac anteriorly. It is thin and runs
attached to it, surrounding fat, blood vessels and almost parallel with medial wall of the other orbit.
nerves. The orbit is oriented with its apex directed It separates the orbit from the anterior, middle
postereo-medially and the base at the front of the posterior and sphenoid air cells.
skull. The medial walls are almost parallel with The floor of the orbit separates it from the
each other and to the sagittal plane. The lateral maxillary sinus. It contains the infraorbital sulcus,
walls are roughly at an angle of 90° to each other. which is continuous with the infraorbital fissure.
Dimensions of the orbit are shown in Table 1.1.
LOCAL ANESTHESIA IN PERIORBITAL SPACE
Awareness regarding the size and volume of
the globe is required while administering local
anesthesia (peribulbar or retrobulbar blocks) in
order to lessen the danger of perforation especially
if the axial length of the eyeball is expected to
be increased (e.g. high myopia, staphyloma).
Retrobulbar hemorrhage, proptosis and increased
intraocular pressure may result with puncture of
the ophthalmic veins. Puncture of the meningeal
coverings of the optic nerve may result in the
anesthetic agent entering the subarachnoid space
and may cause respiratory depression.8 Use of
a semi-sharp needle and a 5/8-inch needle for
peribulbar anesthesia may reduce the frequency of
such complications directed away from the eyeball. Figure 1.5 Left bony orbit
Figure 1.6 Medial wall of the orbit Figure 1.7 Lateral wall of the orbit
Table 1.2 Walls of the orbit
Orbit Composing structures Relations

Superior wall Orbital plate of the frontal bone, sphenoid bone (lesser Frontal air sinuses and frontal
wing) lobes of the brain
Inferior wall Orbital plate of maxilla, orbital surface of the zygomatic, Maxillary air sinus
orbital process of palatine bone
Medial wall Maxilla(frontal process), lacrimal bone, ethmoid Sphenoid air sinuses
(orbital plate) and sphenoid body
Lateral wall Zygomatic and sphenoid greater wing -
It runs forward and passes below the surface as (Fig. 1.8).12 These limited spaces are crowed with
the infraorbital canal to open below the orbital a number of blood vessels and nerves passing
margin as the infraorbital foramen. through. Thus lesions often present as a syndrome
The lateral walls are composed of the called “orbital apex syndrome” (Tables 1.3 and
zygomatic anteriorly and the greater wing of 1.4). 10
the sphenoid posteriorly. They are triangular in
shape with base present anteriorly and lie at an
approximate angle of 90° with each other.10
SPREAD OF INFECTION AND MALIGNANCY INTO
THE ORBIT AND ORBITAL WALL FRACTURES
The medial wall may often be the route through which
infections spread from the ethmoidal sinuses into the
orbit since it is thin as paper, though it is the floor
of the orbit that is most often involved in traumatic
blow-out fractures. Maxillary sinus tumors may also
spread into the orbit through the floor. The floor of
the orbit is often involved in blowout fractures.
Apertures
The pyramidal structure of the orbit is incomplete
due to the presence of a number of apertures Figure 1.8 Apertures in the orbit
Table 1.3 Apertures in the bony orbit
Aperture Location Boundaries Contents Surgical Importance

Superior orbital Between the roof Greater and lesser wings Superior and inferior divisions of the IIIrd, Lesions that frequently present with
fissure and lateral wall of of the sphenoid and closed IVth, VIth cranial nerve, the lacrimal, frontal multiple cranial nerve palsies along
the orbit off laterally by the frontal and nasociliary branches of the Vth cranial with loss of vision are called the
bone nerve, superior and inferior branch of orbital apex syndrome (OAS)
ophthalmic vein and sympathetic fibers of the The cavernous sinus syndrome
cavernous plexus may include features of OAS, and
also Vth nerve involvement with
Inferior orbital Lateral wall and the Maxilla, the palatine bone
also involvement of sympathetic
fissure floor of the orbit and and the greater wing of the
fibers. They may occur in
ending about 2 cm sphenoid
association with injuries to the
from the anterior
facial bones, skull fractures,
margin of the orbit
inflammatory conditions and
Optical canal Apex of the Roots of the lesser The optic nerve along with its sheathings of orbital apical tumors
pyramidal wings of the sphenoid dura, arachno and pia mater, the ophthalmic The Superior Oblique fissure or
orbit structure, and medially the body of artery and a few fibers of sympathetic nerves Rochon-Duvigneaud syndrome
directed forwards, the sphenoid. Posterior that pass along with the artery involves lesions anterior to the
downwards and ethmoid air cells (Onodi apex, including the annulus of
laterally cells) may form the Zinn. However, the optic nerve
medical wall in certain and vision is left intact
instances The optic nerve may also be
Anterior Between the roof Frontoethmoidal suture Anterior ethmoidal vessels and nerves damaged in its intra canalicular
Ethmoidal and medial walls of between the medial and portion of the optic canal
Canal the orbit superior orbital walls Ethmoid sinus surgery may cause
optic nerve damage in cases
where ethmoid air cells form the
canal wall
Posterior Between the roof Frontoethmoidal suture Posterior ethmoidal vessels and nerves Vessels may bleed during
Ethmoidal and medial walls of between the medial and extraperiosteal medial wall
Canal the orbit superior orbital walls dissection and thus need to be
clipped or cauterized
Anatomical and physiological basis of ocular pharmacotherapy
7
Table 1.4 Causes of orbital apex syndrome
Inflammatory Infectious ** Neoplastic Traumatic/ Iatrogenic Vascular

1. Sarcoidosis Fungi: Aspergillosis, Head and neck tumors: Traumatic 1. Carotid cavernous aneurysm
2. Systemic lupus Mucormycosis Nasopharyngeal carcinoma, 1. Penetrating injury 2. Carotid cavernous fistula
erythematosus Bacteria: adenoid cystic carcinoma, 2. Nonpenetrating injury 3. Cavernous sinus thrombosis
3. Churg-Strauss Streptococcus species, squamous cell carcinoma 3. Orbital apex fracture 4. Sickle cell anemia
syndrome Staphylococcus species, Neural tumors: Neurofibroma, 4. Retained foreign body
4. Wegener Actinomyces species, meningioma, ciliary neurinoma, Iatrogenic
granulomatosis Gram-negative schwannoma
1. Sinonasal surgery
5. Tolosa-Hunt bacilli, anaerobes, Metastatic lesions:
2. Orbital/facial surgery
syndrome (THS)* Mycobacterium 1. Lung, breast, renal cell,
6. Giant cell arteritis tuberculosis malignant melanoma
7. Orbital inflammatory Spirochetes: Treponema 2. Hematologic: Burkitt lymphoma,
pseudotumor pallidum non-Hodgkin lymphoma,
8. Thyroid orbitopathy Viruses: Herpes zoster leukemia
3. Perineural invasion of cutaneous
malignancy
*THS is a syndrome characterized by painful ophtalmoplegia due to granulomatous inflammation of unknown etiology affecting the cavernous sinus or orbital
apex.
** Infections may spread from the paranasal sinuses, periorbital structures of the CNS. Cavernous sinus thrombosis may occur by spread of bacterial
infections from the paranasal sinuses, while fungal infections should be suspected in patients with immunosuppression, diabetes mellitus, and hematologic
malignancies.
Malignancies may spread from a primary The Cornea
ocular or orbital source or from adjacent paranasal
sinuses. Metastasis especially in the cavernous The cornea is an avascular 50–60 micron-
sinus may also occur. Local spread from head and thick structure composed of 5 layers—corneal
epithelium, anterior limiting lamina, substantia
neck tumors may also occur.
propria, posterior limiting lamina and endothelium
Surgical intervention in sinonasal and
(Fig. 1.9). Since it is an avascular structure it
periorbital procedures have also on occasion
obtains nutrition by diffusion from neighboring
produced orbital apex syndrome (OAS). aqueous humor. It is transparent, strong and
relatively resistant to abrasions. A tear film covers
CONTENTS OF THE BONY ORBIT the surface of the cornea. Corneal epithelial
layer is composed of a basal columnar germinal
The Globe layer, intermediate wing cells and an outer layer
of squamous, non-nucleated cells. These cells
The globe is located within the bony orbit. It is form a continuous layer over the cornea due to
roughly spherical in shape, being composed of the zona occludens type of tight junctions that
the transparent cornea anteriorly and the opaque they form. Interstices present between these cells
sclera posteriorly. It is 2.5 cm in diameter and has communicate directly with the aqueous humor.
a volume of approximately 25 mL. The cornea Adhesion of the basal layer to the anterior limiting
has a greater curvature as compared to the sclera, membrane or Bowman’s membrane is facilitated
and has a radius of about 7.8 mm. The sclera is by network of anchoring fibrils and plaques. Cells
the larger of the two components and is part of a from the basal layer are able to regenerate and
sphere of radius about 11.5 cm. replace other cells. The rate of corneal epithelial
turnover is approximately 5–7 days.11
HYPERMETROPIA AND MYOPIA
The main bulk of the substantia propria is
composed of type 1 collagen fibers arranged in
Small globe size may result in hypermetropia, a
refractive error caused when the image of objects
bundles that help maintain the structure of the
viewed falls beyond the retina. Large globe size may cornea. They also form a strong junction with the
result in myopia, where the image of objects viewed sclera and thus maintain intraocular pressure and
falls in front of the retina. alignment of the visual apparatus including the lens.
A network of fibroblast cells called keratocytes, is
The globe is composed of an external layer found in the stroma, connected to each other by gap
made up of the sclera, a middle choroid layer junctions. These cells have well developed rough
and an inner retina. The sclera consists of dense endoplasmic reticulum and Golgi apparatus. Their
collagenous tissue mixed with a few elastic main function is the secretion and maintenance
fibers. At the limbus or corneoscleral junction, of the stroma. Hydrophilic molecules pass easily
it continues anteriorly as the transparent cornea. through the stroma, whereas the epithelial layers
The choroid or “middle” layer of the globe lies are more permeable to lipophilic molecules.
in close approximation to the sclera. Anteriorly, Corneal endothelium lines the inner surface of
behind the transparent cornea, it is present as the the cornea. It is composed of a single layer of
iris and ciliary body. flattened polygonal cells whose main function is to
The retina is the light sensitive layer of the allow passage of large amount of water, solute and
eye, containing light receptors and neural tissue. molecules of size 1000000 Da and below. It is also
The globe contains the crystalline lens, the capable of pinocytosis. A fluid pump responsible
anterior chamber between the cornea and the iris, for the rapid rates of fluid transport is thought to
the posterior chamber between the iris and the be a HCO3– based transport linked to the Na+ K+
ciliary body and the vitreous chamber between ATPase. It is thought to maintain the amount of
the lens and the retina. fluid in the stroma and prevent stromal edema from
Figure 1.9 Cornea
occurring. Aquaporins (AQP1) have also been Tenon’s Capsule

identified in the endothelium and thought to play
a role in maintaining corneal thickness. A fascial membrane called Tenon’s capsule
The absence of blood vessels and the surrounds the globe of the eye, separating it
particular arrangement of epithelial cells and the from the orbital fat (Fig. 1.10). It extends from
extracellular matrix are largely responsible for the point where optic nerve exits the globe to
the smoothness and transparency of the cornea. the corneoscleral junction where it fuses with
Cornea also contributes most of the refractive the conjunctiva. It is pierced by tendons of the
power of the eye. Changes in its curvature may extraocular muscles and it becomes continuous
result in a refractive error called astigmatism. with their fascial coverings. It is divided into an
Though it is avascular, the cornea is well anterior and posterior space by the tendons of the
supplied by sensory fibers from the trigeminal extraocular muscles and their fascia. A number of
nerve. Fibers loose their sheaths near the limbus fascial septa arise from the eyeball and are fixed
and run through the cornea radially. As they to the periosteum, separating the orbital fat into
loose the sheaths there is no interference with the various compartments. They help in maintaining
corneal transparency. Corneal epithelium has one the position of the eye and the position of the
of the densest nerve supplies of all epithelia. Loss orbital fat and hence assist in binocular vision.
of innervation of the cornea leads to neurotrophic
keratitis and loss of corneal epithelium.
SUB-TENON’S ROUTE OF DRUG ADMINISTRATION
A sub-Tenon’s capsular approach may be used
TRANSCORNEAL DRUG ABSORPTION for delivery of anesthetic, steroid and antibiotic
Transcorneal drug absorption is the main route of medications, by incising the conjunctiva and entering
drug delivery to the intraocular tissue. It forms a the episcleral space just inside the inferior border
lipid-water-lipid trilayer barrier to transcorneal drug of the orbital margin. This route of administration
absorption. The corneal epithelium provides easy carries a lower risk of penetration of the globe. The
entry to lipophilic drugs; stroma is more permeable anesthetic agent acts directly on scleral nerves as
to hydrophilic drugs while endothelium is more well as spreads into the extraocular muscles and
permeable to lipophilic drugs. Therefore, drugs must also through the thinner portions of the posterior
have both the lipophilic and hydrophilic properties to capsule to block the extraocular muscles, the motor
penetrate well through cornea. and sensory nerves.12
Figure 1.10 Tenon’s capsule
The Sclera pressure. Interspersed between the collagen fibrils

are scleral fibrocytes. They have long cytoplasmic
The sclera is a tough, opaque fibrous structure, processes that form gap junctions with other
protecting the contents of the globe. It is continuous fibrocytes and are responsible for secretion and turn
with the cornea at a junction known as the limbus. over of the extracellular matrix material. They are
It permits a limited amount of drug absorption, due activated by injury.13
to its vascularity. It is covered by the conjuctival
epithelium reflecting onto it from the inner surface TRANSSCLERAL DRUG PERMEATION
of the eyelids. Posteriorly it is pierced by the optic The cellular structure of sclera provides an easier
nerve passing through a sieve like perforated plate. penetration to drugs as compared to cornea and
Anteriorly at the limbus, an endothelial canal called conjunctiva. Therefore, subconjunctival and sub-
the canal of Schlemm is present. Externally, the Tenon’s route of drug administration provide better
intraocular bioavailability as compared to topical
sclera is covered by Tenon’s capsule. Within this route of administration.
layer is present the episclera, followed by scleral
stroma. The innermost layer is called lamina fusca, The scleral spur is formed by a ring of deep
which is closely applied to the choroid. Sclera is fibers of the sclera surrounding the limbus.
composed of Type I and III collagen fibril with It receives insertions of the trabecular tissue
small amounts of type V and VI. These fibrils are anteriorly, and posteriorly parts of the ciliary
surrounded by a matrix composed of decorin and muscle are inserted into it. Thus, contraction
biglycan. They are proteoglycans. Collagen fibers of the ciliary muscle facilitates opening of the
are interwoven and are also mixed with fibers from trabecular network. The optic nerve pierces
the insertions of the extraocular muscles. This the sclera posteriorly. Outer scleral fibers join
particular arrangement of fibers gives the sclera the dural covering of the optic nerve. Lamina
its physical and mechanical properties. It is able to cribrosa is formed by the remaining fibers. They
maintain shape while being subjected to the pull also form small canals through which fibers of
of extraocular muscles as well as accommodate the optic nerve exit the eye. A centrally located
minor changes in shape due to changing intraocular canal conveys the central retinal artery and vein.
Though the posterior ciliary blood vessels and epithelium of the posterior surface is bilayered,
nerve pass through the sclera, the sclera itself its deeper anterior layer being pigmented to
receives nutrition by diffusion from Tenon’s absorb light. The more superficial posterior layer
capsule and episcleral blood vessel networks is non-pigmented and is in continuity with the
and also from the choroid. However, the sclera unpigmented layer of the retina. The free surface
receives an abundant nerve supply. Thus, scleral of the iris contains numerous grooves, which
inflammation is very painful.13 allow movement of fluid from the posterior to
the anterior chambers.15 The iris is pigmented and
INFLAMMATION OF THE SCLERA
hence absorbs and retains lipophilic drugs. The
Inflammation of the sclera is known as scleritis. The stored drugs are then released slowly.
slow rate of fluid fluxes through the sclera allows
immune reaction to persist for a prolonged duration.
Pathophysiology of scleral disease may involve Innervation of the iris
antigen or immune complex mediated activation of
scleral fibroblasts, which subsequently damages The muscles of the iris are supplied by autonomic
the collagen fibrils and their interactions with nerves. The constrictor pupillae muscle is
proteoglycan molecules. These damaged proteins,
which have all along been sequestered may then
innervated by parasympathetic fibers arising from
be presented to the immune system and provoke the ciliary ganglia. When stimulated the pupil
localized or even systemic disease. They may also constricts, reducing its diameter and causing a
involve an element of vasculitis especially of the five-fold decrease in the amount of light entering
episcleral arterial anastomoses.14
the eye. The dilator pupillae muscle is supplied
by sympathetic autonomic fibers that originate in
Iris and its Muscles the T1 segment of the spinal cord. Preganglionic
fibers pass to the superior sympathetic cervical
The uveal tract is the pigmented middle layer of ganglion. Postganglionic fibers pass along with
the eye. It is continuous with the pia-arachnoid blood vessels and supply the muscle fibers. When
coverings of the optic nerve. The iris and its stimulated, the radial fibers of the dilator pupillae
muscles form the anterior part of the uveal tract. constrict and the pupillary diameter increases.
The iris acts as a diaphragm surrounding the pupil.
It is composed of fibroblasts, melanocytes and
loose collagenous material that contain its nerves
Ciliary Body
and blood vessels. It lies between the cornea and The ciliary body is continuous with the choroid
lens, splitting the anterior segment of the eye into layer of the eye. Its main function is the suspension
an anterior chamber between the cornea and iris of the crystalline lens and the secretion of
and a posterior chamber between the iris and the aqueous humor. It is attached to the scleral spur
lens. The main function of the iris is to control and passes around the eyeball in the irdiocorneal
the aperture of the pupil. The larger the pupillary angle. Hence, anteriorly it is continuous with
aperture is, the more the amount of light entering the tissues of the iris, while posteriorly it forms
the eye and vice versa. The aperture is controlled the ora serrata and continues as the choroid. It
by the sphincter pupillae and dilator pupillae. is brown in color due to the pigment contained
The sphincter pupillae is formed at the rim of the in its epithelial layers. It has the following parts
pupillary margin of the iris by a concentration of (Fig. 1.11)—pars plicata, present anteriorly, which
circularly arranged smooth muscle fibers. The is ruffled and pars plana present more posteriorly,
pupillary aperture decreases upon contraction of which is smooth and continues with the ora serrata.
these fibers. The dilator pupillae muscle fibers Suspensory ligaments of the lens pass into the
increase pupillary aperture when they contract pars plana, anchoring the lens firmly. The ciliary
as their fibers are arranged radially. The anterior body is covered by a bilayer of epithelial cells,
surface of the iris has no epithelial covering. The a superficial unpigmented layer and an inner
cornea, vitreous and lens. It also plays a major
role in the regulation of intraocular pressure and
the general shape of the eyeball. Any alteration
to its drainage and/or secretion causes raised
intraocular pressure.
Secretion of Aqueous Humor: It is secreted
continuously by the epithelium of the ciliary
processes of the pars plicata. They have a large
surface area due to the presence of a number of
folds, as well as an extensive capillary network.
Fluid secretion is a result of active as well as
passive processes. Fluid is essentially filtered
out of the ciliary capillaries into the stroma
and is then secreted by the pigmented and
unpigmented epithelium of the ciliary processes
Figure 1.11 Lens and ciliary body into the posterior chamber of the eye. Here, the
unpigmented epithelium actively secretes Na+
pigmented layer. Ciliary body stroma is composed
ions into the lateral intracellular spaces. Cl– and
of loose collagen bundles and the ciliary muscle.
HCO3– ions follow the positively charged Na+
The ciliary muscle is a ring of muscle tissue. It
ions. Water is drawn out due to the osmolar forces
contains circular, radial and meridional fibers.
developed by these ions.
Nerve supply to the ciliary body and muscle is
Fluid then flows into the posterior chamber
predominantly parasympathetic from the ciliary
and over the edge of the iris in the pupil to enter
ganglion. Upon stimulation, it contracts towards
the anterior chamber. The rate of secretion of
the optical axis, relaxing the suspensory ligaments
aqueous is influenced by intraocular pressure and
causing the lens to bulge and accommodate.16
blood pressure in the ciliary vessels.
PASSAGE OF DRUGS THROUGH IRIS AND Outflow of Aqueous Humor: Fluid exits the
CILIARY BODY anterior chamber through outflow tracts in the
The iris and ciliary body have numerous capillaries iridiocorneal angle (Fig. 1.12). It passes through
that freely allow movement of particles through the trabecular meshwork and then enters the
them. Drugs may enter systemic circulation following canal of Schlemm. From here, it drains into the
ocular administration and systemically administered
drugs may enter into the aqueous through these
extraocular veins. Though it is not a primary
sites. It also contains enzymes that are involved in
the detoxifications of metabolites and drugs, which
are rapidly removed by the high blood supply to the
ciliary body.
Aqueous Humor
It is a fluid formed by the ciliary body and
occupies the anterior and posterior chambers. It
is secreted in the posterior chamber and flows
through the pupil into the anterior chamber
(Fig. 1.12). It drains through the canal of Schlemm
into the episcleral veins. Some fluid may also
leave the anterior segment through the surface
of the iris. It provides nutrition to the avascular Figure 1.12 Outflow of aqueous
route, aqeuous also drains through uveoscleral A capsule surrounds the lens that prevents
outflow, which involves aqueous reabsorption by entry of hydrophilic molecules into the lens,
the ciliary body and iris and ultimately drains into however, lipophilic molecules enter and pass
the veins of the ciliary body, choroid and sclera. through the lens slowly. Hence the lens acts as a
Trabecular meshwork: It is the main site of barrier to the movement of substances from the
resistance to the flow of aqueous and has a unique aqueous to the vitreous humor. After the lens is
system to maintain its patency and prevent occlusion removed, rates of transport are higher between
by debris. A population of phagocytic cells is found the aqueous and the vitreous humor.17
on the trabecular meshwork and also within the canal
of Schlemm that removes debris and other molecules Vitreous Humor
and keeps the drainage pathway clear.
The vitreous accounts for about 80% of the mass
of the eyeball and fills the vitreous chamber. It is
GLAUCOMA
composed of hyaluronan; that is long chains of
An imbalance in the rates of formation and outflow of
aqueous humor leads to an increase in the intraocular
glucosaminoglycan and a few type II collagen
pressure, a known risk factor for glaucoma. In a small fibers. The fibers are anchored to the basal lamina
subset of patients’ intraocular pressure may remain of the ciliary body. It forms the suspensory
normal. One of the common causes of increased ligaments of the lens. At the periphery, it is in
intraocular pressure is an increased resistance to
the outflow of aqueous humor through the canal of
a gel like state and towards the center it is in a
schlemm or open angle glaucoma. It may also occur more fluid state. Hyalocytes are found within
if the iris obscures the outflow tract; in which case, it the vitreous and they produce substance of the
is called the angle closure glaucoma. vitreous. The hyaloid canal occupies a central
position in the vitreous and is the remnant of
Crystalline Lens the hyaloids artery. It runs from the posterior
surface of the lens to the optic disc. Rupture of the
The lens is a transparent biconvex structure, with hyaloids artery may sometimes form structures
a slightly flattened anterior surface and a more called “floaters” that may interfere with vision.
curved posterior surface that is in contact with
the vitreous. It is devoid of any blood vessels or INTRAVITREAL DRUG ADMINISTRATION
nerve fibers that may impede its transparency. Due to poor bioavailability of drugs in the posterior
Its refractive or diopteric power is less than that segment of eye following systemic or other routes of
of the cornea and tears film. The importance of ocular administration, drugs are often administered
the lens is its ability to alter its shape and hence directly into the vitreous chamber to target posterior
segment diseases. The vitreous may serve as a
diopteric power. The lens is encircled by zonular deposit for drugs injected or implanted intravitreally
fibers that attach to the ciliary processes of the or administered by iontophoresis.
ciliary body (Fig. 1.11). Changes in tension in this
tissue are transferred to the lens, and result in the Retina and Optic Nerve
change in its shape and accommodative power.
The lens is composed of lens fibers which The retina is the sensory layer of the eyeball. It
contain crystallin proteins. Crystallins are lies between the choroid and the vitreous. It is
responsible for the transparent, refractile and continuous with the optic nerve at the optic disc
elastic properties of the lens. Fibers toward the and continues anteriorly to cover the iris and
center of the lens form the nucleus of the lens, ciliary body. It is composed of the pigment layer
while those towards its margin (equator) form in opposition to the choroid, followed by the rods
the cortical portion of the lens. Fibers terminate and cones, external limiting membrane, outer
in sutures found on the anterior and posterior nuclear layer, outer plexiform layer, inner nuclear
surfaces of the lens. layer, inner plexiform layer, ganglion cell layer,
nerve fiber layer and an inner limiting membrane, eyelid. Individual muscles and their actions are
in contact with the vitreous. described below.
The blood retinal barrier: Cells of the pigment
layer form zona occludens type tight junction with The Rectii
each other and prevent movement of a number of They arise from a common tendinous ring
particles between the vitreous and the choroid. around the margins of the optic canal called the
This function is somewhat in continuation of the annulus of Zinn. Each muscle passes anteriorly
function of the blood–brain barrier as the retina in positions corresponding to their names and
may be considered to be part of the brain. The attach onto the sclera behind the corneoscleral
blood retinal barrier properties are also determined junction. They receive their blood supply from
by the endothelial cells of its capillaries. They are the ophthalmic artery and its branches. The lateral
of the continuous type and provide a barrier to the rectus is supplied by the abducent nerve, while the
transport of metabolites and toxins in the blood. oculomotor nerve supplies the others.
It is a barrier to hydrophilic drugs but lipophilic
drugs cross easily. Therefore, orally administered
drugs and other systemic agents may be present The Superior Oblique
in the eye and sometimes cause retinal toxicity, Its origin is superomedial to the optic canal on the
e.g. digitalis, phenothiazines, methyl alcohol, body of the sphenoid. It passes forward through the
quinoline derivaties, sildenafil. trochlea on the superior orbital margin. It passes
posterior and laterally and inserts into the sclera
Extraocular Muscles between the insertions of the superior and lateral
rectii. It is supplied by the trochlear nerve and
There are 7 extraocular muscles in total ophthalmic artery and the maxillary artery.
(Fig. 1.13). There are 4 rectii (superior, inferior,
medial and lateral), and 2 obliques (superior
and inferior) that attach to the globe and allow The Inferior Oblique
its movements, while the seventh is the levator It arises from the orbital surface of the maxilla,
palpebrae superioris that attaches to the upper lateral to the nasolacrimal groove. It passes
Figure 1.13 Extraocular muscles

posteriorly, laterally and upwards to insert oblique, the nasolacrimal sac and eyelids, and
between insertions of the inferior and lateral rectii. also from the eyeball. It drains into the cavernous
sinus, sometimes joining the superior ophthalmic
The levator palpebrae superioris vein. It also communicates with the pterygoid
plexus and the facial vein.
It arises above the optic canal, passes anteriorly
and inserts into the skin and the tarsal plate of
Lymphatic drainage and Immune
the upper eyelid. It has a component of smooth
muscles, which receive sympathetic innervation privilege of the eye
(Muller’s muscle). Its other fibers are supplied by Lymphatics draining the conjunctive only
the oculomotor nerve. It receives its blood supply have been identified. Furthermore, the eye is
from the ophthalmic artery. a site of immune privilege. That is, potentially
immunogenic tissues in the eye survive over
Movements of the globe prolonged intervals of time without provoking
an immune reaction. It is believed that such a
Together, the rectii and obliques are responsible
phenomenon occurs in order to protect an organ
for elevation, depression, adduction and abduction
or tissue essential for the survival of the host,
of the eyeball. Individual muscles may require to
since loss of sight may have life-threatening
be tested to ensure that a particular nerve has been
consequences.
blocked by application of an anesthetic agent.
Factors that may explain this privilege is
the presence of a relatively robust blood-ocular
Blood Supply and Lymphatic barrier that prevents mechanically entry of
Drainage antigens and proteins from the blood stream.
There is also a lack of lymphatic vessels within
Arterial supply the eye, and aqueous humor drains directly into
The ophthalmic artery, a branch of the internal venous blood and not to regional lymph nodes.
carotid artery, and its branches supply blood to However, even though there is an absence of any
the orbit and its structures, along with branches defined anatomic lymphatic drainage pathway in
of the maxillary artery. The important branches of the eye; there appears to be a functional pathway
the ophthalmic artery include the central retinal as has been recently shown. Aqueous humor is
artery, branches to the muscles, the ciliary arteries itself rich in inflammatory molecules such as
(anterior and long and short posterior branches), TGF-b2. Anterior chamber-associated immune
the lacrimal artery, supraorbital branch, the deviation (ACAID) is also quoted to demonstrate
anterior and posterior ethmoidal arteries, the that immunosuppressive environments operate in
meningeal, medial palpebral, supratrochlear and the eye. That is, antigen-presenting cells derived
dorsal nasal artery. from the eye are altered by exposure to various
cytokines in the eye and that suppress any future
Venous Drainage exposure to a similar antigen derived from the
eye. Ocular tissues also express Fas ligands that
Superior and inferior ophthalmic veins and the induce apoptosis of Fas+ immune cells that may
infraorbital vein are the main veins of the orbit. enter the eye. It appears that neural input also
The superior ophthalmic vein is formed by the facilitates the immune privilege of the eye.14
facial and the supraorbital vein. It also receives
the central retinal vein and drains into the
Innervation
cavernous sinus. The inferior ophthalmic vein is
formed on the floor of the orbit, anteriorly and The structures of the orbit receive motor inner
receives tributaries from the inferior rectus and vation from fibers that are somatic as well as
autonomic. The optic nerves carry the sense On the other hand, stimulation of the
of sight while other structures in the orbit parasympathetics causes pupillary constriction
are receiving somatic sensory innervation via the action of the constrictor pupillae. This
by the ophthalmic division of the trigeminal action is mediated via the muscarinic receptors.
nerve. The ophthalmic nerve has three main Parasympathetic stimulation also leads to
branches; the lacrimal nerve, the frontal nerve accommodative changes in the lens. Stimulation of
and the nasociliary nerve. The conjunctiva and the parasympathetics to the eye causes contraction
the skin covering the lateral part of the upper of the ciliary muscle. Contraction of the ciliary
eyelid are supplied by the lacrimal nerve. The muscles provides a sphincter-like action, reducing
frontal nerve supplies the skin of the upper its diameter around the suspensory ligaments of
eyelid and conjunctiva. The skin of the lower the lens. The ciliary ligaments then relax and
eyelid is supplied by the infraorbital branch of the lens assumes a more spherical shape with a
the zygomatic nerve, which is a branch of the higher refractive power. The eye is thus able to
maxillary nerve. The cornea, sclera, iris and adjust focal length and view near objects clearly.
ciliary body are supplied by the nasociliary nerve. Since the ciliary body receives predominantly
Somatic motor innervation is provided by the parasympathetic nerve supply, accommodation
oculomotor, abducent and trochlear nerves to the is controlled by parasympathetic autonomic
extraocular muscles. The lateral rectus muscle nerves. A concomitant reduction in the pupillary
is supplied by the abducent nerve, the superior size accompanies accommodative changes in the
oblique by the trochlear nerve while all others are ciliary body and lens, due to stimulation of the
supplied by the oculomotor nerve. constrictor pupillae.
The ciliary ganglion: The ciliary ganglion is
EFFECT OF DRUGS ON PUPIL SIZE AND
located in the orbital fat near the apex. It has three
ACCOMMODATION
main roots; they are the sensory, sympathetic
Cholinomimetic drugs cause miosis due to
and motor or parasympathetic. The sensory root
contraction of circular muscles of iris and spasm of
arises as branches from the nasociliary nerve and accommodation due to ciliary muscle contraction.
passes through the ganglion to supply the sclera, Cholinergic blockers have opposite effects, i.e.
cornea, iris and ciliary body. The sympathetic root mydriasis and paralysis of accommodation.
Sympathomimetics cause mydriasis due to radial
arises from postganglionic neurons around the
muscle contraction but accommodation remains
sympathetic plexus of the internal carotid arteries, unaffected.
and passes through the ganglion emerging as short
ciliary nerves to supply the blood vessels of the
eyeball and the dilator pupillae muscles of the THE VISUAL PATHWAY
iris. The parasympathetic root is derived from
preganglionic fibers of the Edinger-Westphal Impulses generated by the rods and cones of the
nucleus and travels with the oculomotor nerve to retina leave each eye via the optic nerve. Fibers
the orbit. Here a branch separates and joins the carrying impulses from the nasal halves of each
ciliary ganglion. Postganglionic parasympathetic retina cross over to the opposite sides at the optic
fibers arise from the ganglion and pass with the chiasma, while fibers from the temporal halves of
short ciliary nerves and supply the sphincter each retina pass on uncrossed. Thus fibers from
pupillae and the ciliary body. the right halves of both the retinae pass in the right
Sympathetic stimulation causes pupillary optic tract, while the fibers of the left halves both
dlilation via α1 adrenergic receptors in the dilator the retinae are carried in the left optic tract (Fig.
pupillae fibers of the iris. The pupillary aperture 1.14). Fibers continue on in the optic tract, and
increases as also the amount of light entering relay at the lateral geniculate body of the thalamus.
the eye. Fibers from this nucleus pass on to the occipital
Figure 1.14 Visual pathway
cortex via the optic radiations (geniculocalcarine eye by a factor of about 1 to 30 and hence aids in
fibers) to the primary visual cortex. Impulses also dark adaptation. Dilator pupillae muscle fibers are
enter various other pathways: fibers from the optic supplied by sympathetic fibers originating from
chiasma; pass on to the suprachiasmatic nucleus; the intermediolateral gray horn of T1 thoracic
the pretectal nucleus to coordinate the pupillary segment, through the superior cervical ganglion.
reflexes, superior colliculus for eye movements Postganglionic fibers pass along with blood
and also to the ventral lateral geniculate body.18 vessels and supply the muscle (Fig. 1.15).
Indirect reflex: When light is shone in one eye, a
PUPILLARY LIGHT REFLEX pupillary reflex is observed in the unilluminated
eye as well. It is called the consensual or indirect
Direct reflex: When light is shone in one eye, pupillary reflex. Fibers from the pretectal nucleus
the pupil constricts. The diagram representing supply the Edinger-Westphal nucleus of both
the pupillary light reflex pathways is shown sides, hence leading to the consensual or indirect
in Figure 1.15. Impulses travel to the pretectal pupillary reflex.19
nucleus, and from here to the Edinger-Westphal
nucleus, parasympathetic fibers arise here and Accommodation and Pupillary
pass back to the constrictor pupillae muscle with
the oculomotor nerve, and through the ciliary
Aperture
ganglion. Alteration of the pupillary diameter A high degree of visual acuity is permitted by
grossly affects the amount of light that enters the the accommodation mechanism. This mechanism
Figure 1.15 Pupillary and accommodation reflex pathways
involves the contraction or relaxation of the Management, Diagnosis and Surgery. New York:
ciliary muscle, and adjustments in the focal Springer Science and Business Media, Inc. 2006;
length of the lens allowing the eye to maintain pp.11–6.
acuity of vision at all times. There appears to 6. Lemp MA. Chapter 6, The tear- deficient patient.
be a feedback mechanism related to chromatic In: Cohen AJ, Mercandetti M, Brazzo BG (eds).
aberration, where a difference in the ability of the The Lacrimal System: Management, Diagnosis and
lens to focus red and blue light acts as a signal to Surgery. New York: Springer Science and Business
correctly adjust the focal power of the lens. Also, Media, Inc. 2006. pp. 99–109.
7. Forrester JV, Dick AD, MacMenamim PG, Lee
convergence of both eyes occurs at the same time.
WR. Chapter 1, Anatomy of the eye and orbit. In:
Pupillary diameter also adjusts along with the
The Eye: Basic Science in Practice, 2nd (edn).
accommodation process.
Saunders; 2002. pp. 2–9.
8. Hamilton RC. Chapter 6, Complications of
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Practice, 39th edn. Elsevier Churchill Livingston.
2005. Chapter 42, pp. 706–8.
ChapteR 2
Routes of Ocular Drug Administration
overview eyelid is gently pulled away from the globe and

a drop of medication is instilled in the cul-de-
Routes of drug administration for the treatment of sac. Patient is asked to look down and gently
ophthalmic conditions are chosen with an objective close the eyes. Keeping the eyes closed for 1
of maximizing the amount of drug reaching its site minute after instillation prevents drainage into
of action in sufficient concentration. Drugs can be the nasolacrimal system. Additionally, pressure
administered to ocular tissue by various routes, applied on the medial canthus with closed
which include: eyes, prevents quick outflow of drug into the
1. Topical lacrimal system. Care should be taken to avoid
2. Periocular: Subconjunctival, Sub-Tenon’s, contamination during drug instillation.
Peribulbar, Retrobulbar Instillation of eye drops is the most convenient,
3. Intraocular: intracameral, intravitreal least invasive and least expensive method of drug
4. Systemic administration to the eye. Topical application also
provides higher ocular drug concentration in the
Topical anterior segment as compared to that achieved
after systemic administration. The topical
Topical application is the most favored route application of 0.3% isotonic tacrolimus eye drops
of ocular drug administration especially when in rats was shown to provide significantly higher
targeting the ocular surface and anterior segment aqueous levels of the drug as compared to that
diseases. Drug solutions and suspensions are achieved after its systemic administration at a
applied topically by instillation on the ocular dose of 0.1 mg/kg/day for 3 days. At the same
surface. Gels and ointments are also popular dosage time the serum levels were significantly high in
forms for topical drug administration. Inserts orally treated animals compared to those treated
placed in the fornices and other drug impregnated topically.2 Similarly, in human, topically applied
devices such as contact lenses applied to ocular gentamicin was shown to provide significantly
surface are also the means of topical drug delivery. higher drug concentration in cornea compared
In order to maximize therapeutic benefit to that after systemic administration.3 However,
of topically applied drugs, it is important to some drugs like ciprofloxacin have been shown
practice an optimum method of drug instillation. to achieve comparable aqueous levels after oral
Based on the tear flow patterns, Fraunfelder and topical administration.4
(1976) described the method for topical drug Topical administration often provides
administration, which can maximize the duration inadequate drug concentration in the treatment
of drug retention in the cul-de-sac.1 Accordingly, of posterior segment diseases especially so
with the patient’s head tilted backwards, the lower in uninflamed eye. Vitreous concentration of
gatifloxacin 0.5% and moxifloxacin 0.3%, after are slowly absorbed. Under topical anesthesia,
topical instillation in uninflamed human eye, the drug solution is injected under the bulbar
was found to be lower than 90% minimum conjunctiva, adjacent to sclera. By injecting the
inhibitory concentration of most common drug subconjunctivally, conjunctival and corneal
bacterial pathogens causing acute postoperative permeability barriers are bypassed. The sclera
endophthalmitis. 5 Although, dexamethasone- is highly permeable particularly for hydrophilic
cyclodextrin eye drops were found to deliver molecules and, therefore, required ocular tissue
significant amounts of dexamethasone to the concentration of drug is quickly achieved with
retina in rabbit eye 6, repeated instillation of subconjunctival route. Moreover, high corneal
dexamethasone sodium phosphate failed to drug concentration is also achieved by diffusion
provide significant vitreous concentration in and leakage through the injection site.
human.7 Subconjunctival injections have been shown
Topical administration carries the advantage to produce high, transient and short lasting
of avoiding systemic exposure to high serum peak concentration as compared to topical
levels of drug and hence systemic adverse effects administration, which produces moderate but
are minimized. For example, systemic use of sustained drug concentration over the period of
genciclovir is associated with hematologic toxicity treatment.9 Clinical efficacy of antibiotics in the
and, therefore, has limited use in the treatment of treatment of bacterial corneal ulcer has been shown
herpetic keratitis. However, topically applied gel to be comparable after subconjunctival and topical
provides high ocular tissue concentration and is administration. 9,10 However, subconjunctival
highly effective against herpetic keratitis without route of administration is indicated in patients
significant risk of hematologic toxicity.8 For some with severe infection or impending corneal
drugs like dexamethasone, systemic absorption perforation to ensure drug delivery especially in
after topical administration in rabbits has been non-compliant patients. Similar observations have
shown to be comparable to that after systemic also been made for other drugs like lidocaine.
administration.6 However, similar results were not Subconjunctival as well as topical administration
observed after topical application in human eye.7 of lidocaine 2% provided equivalent pain
The drug penetration into the ocular tissue relief in patients receiving intravitreal injection
after topical application is affected by several of triamcinolone. 11 In some cases, however,
factors, which are discussed in chapter 3. subconjunctival administration has been shown
to provide better efficacy compared to topical
administration. For example, anti-VEGF
Periocular antibodies showed significantly higher efficacy
Periocular route of administration is used to inject in reducing neovascularization and corneal graft
drugs in the vicinity of globe without penetrating rejection in rats after subconjunctival injection
it. Periocluar routes of administration include compared to topical administration.12 In other
subconjunctival, sub-Tenon’s, peribulbar and cases, combination therapy using subconjunctival
retrobulbar. The anatomical details of the orbit along with topical administration has been shown
and globe are important while injecting drugs in to have higher efficacy as compared to topical
the periocular region. Relevant anatomical details alone. In patients with fungal keratitis, topical
are discussed in chapter 1. amphotericin with subconjunctival fluconazole
provided better efficacy as compared to topical
amphotericin alone.13
Subconjunctival
Subconjunctival injections provide
Subconjunctival injections are used for ocular significantly higher ocular tissue concentration
delivery of drugs that penetrate cornea poorly or as compared to systemic route of administration.
Routes of Ocular Drug Administration 23
In one of the studies, 53 patients received 20 in sub-Tenon’s space in anterior, mid and posterior
mg of vancomycin subconjunctivally and 47 positions using cannulae with increasing length.
received two doses of vancomycin intravenously Anterior sub-Tenon’s injections do not offer much
(1 g twice a day). The peak aqueous humor advantage over subconjunctival injections.
levels of vancomycin were significantly higher Sub-Tenon’s is a commonly used route
and were achieved earlier after subconjunctival of administration of local anesthetics for
administration compared to intravenous. 14 ophthalmic surgery. For the administration of
Retinal delivery of drugs is also higher after regional anesthesia for surgical procedures
subconjunctival injection as compared to systemic all three approaches, i.e. anterior, mid and
administration. For example, retinal concentration posterior, have been described. Anterior, mid as
of celecoxib was significantly higher after well as posterior injections provide equivalent
subconjunctival injection compared to that akinesia and intraoperative pain relief, however,
achieved after intraperitoneal administration in the retention of lid closure is significantly
rats.15 higher with anterior and mid injection as
Although, subconjunctival administration compared to posterior. Posterior injection
of drugs is less invasive than intraocular drug is more painful than anterior but the risk of
administration, it is associated with several chemosis and conjunctival hemorrhage is
complications. Subconjunctival Injections significantly higher with anterior than mid and
cause irritation and pain at the site of injection. posterior injections.16 Sub-Tenon’s block has
Subconjunctival injection can also cause shown higher efficacy as compared to topical
subconjunctival hemorrhage, granuloma, necrosis anesthesia. In a double-blind randomized clinical
and conjunctival scarring. Severity of conjunctival trial involving 210 patients, the extent of patient
toxicity is also determined by the pH and discomfort and intraoperative complications
osmolarity of the injected solution. Inadvertent after routine cataract surgery under sub-Tenon’s
globe penetration and intraocular administration or topical anesthesia were compared. All patients
is also a concern. underwent phacoemulsification and intraocular
lens implantation. Postoperative pain assessment
Sub-Tenon’s immediately after surgery and 30 minutes
Sub-Tenon’s route of administration is used to later showed that sub-Tenon’s block provided
inject drugs under Tenon’s capsule. Tenon’s significantly greater pain relief at both time
capsule is a thin membrane like fascia that points. Intraopertaive complications, however,
surrounds the globe and separates it from the were the same in both groups. 17 In another
orbital fat. Between the inner surface of Tenon’s randomized clinical trial involving 59 patients
capsule and outer surface of sclera lies a potentials undergoing trabeculectomy, topically applied 2%
space known as sub-Tenon’s or episcleral space. lignocaine jelly was as effective in pain relief
Numerous delicate bands of connective tissue as lignocaine 2% administered by sub-Tenon’s
cross this space and attach the Tenon’s capsule to route.18
sclera. Anteriorly, the fascia fuses with the sclera Sub-Tenon’s block has also been found useful
about 1.5 cm posterior to corneoscleral junction. for vitreoretinal surgical procedures. 19 Sub-
Posteriorly, it fuses with the meningeal covering Tenon’s route of administration is also widely
of the optic nerve. The posterior part of Tenon’s used to administer drugs like triamcinolone
capsule is thinner than the anterior part and may acetonide when targeting posterior segment.
become fenestrated with advancing age. Single sub-Tenon’s injection of triamcinolone
Sub-Tenon’s drug administration provides acetonide provides therapeutic concentrations
high intraocular drug levels by exploiting the in the posterior segment especially the retina
permeability of sclera. The injection can be made and choroid for 30 days.20 However, the drug
concentration achieved in the retina is lower Tenon’s block, peribulbar block is more efficacious
as compared to intravitreal administration but is associated with more technique related
and in patients with bilateral diffuse diabetic complications because the sun-Tenon’s route uses
macular edema, intravitreal administration of a blunt cannula and infiltration is superficial.26,27
triamcinolone acetonide provided better visual Peribulbar route is also used for injecting
outcome as compared to sub-Tenon’s injection.21 drugs like triamcinolone acetonide in conditions
Similarly, intravitreal triamcinolone acetonide such as diabetic macular edema and Graves
was also found to be more effective than posterior ophthalmopathy.28,29 Peribulbar injections can
sub-Tenon’s injection in the treatment of branch cause periorbital ecchymosis and conjunctival
retinal vein occlusion.22 chemosis. The incidence of retrobulbar
The complications associated with sub-Tenon’s hemorrhage, optic nerve injury, and inadvertent
injection include pain on injection, swelling, intraocular or subdural injection is less as
pseudoptosis and subconjunctival hemorrhage. compared to retrobulbar injection.
Backflow of the injected drug through the Superficial peribulbar injection is a modified
incision has also been reported and this could technique whereby the injection is made using a
lead to reduced efficacy and adverse effects.23 The half-inch 25-gauge needle under the conjunctiva
technique of administering sub-Tenon’s injection about 5 mm from the limbus inferiorly with
is more difficult than other periocular injections needle directed towards the inferior wall of the
as it requires accurate placement of the cannula orbit. The technique provides a quicker onset
in the potential sub-Tenon’s space close to sclera. of action and higher efficacy as compared to
This increases the incidence of ocular penetration. conventional peribulbar block possibly due to
Ocular penetration and inadvertent intraarterial spread of drug solution into the sub-Tenon’s
injections can result in severe complications such space. Subconjunctival hemorrhage is the main
as central retinal arterial occlusion and retinal and side-effect of this route of administration.30
choroidal vascular occlusion.24,25
Retrobulbar
Peribulbar Retrobulbar route of administration delivers drugs
Peribulbar route of administration is mainly used behind the globe inside the muscle cone. For
for injecting local anesthetic agents for surgical retrobulbar injection, needle is inserted midway
procedures. The 6 extraocular muscles form a between the lateral canthus and lateral limbus
muscle cone behind the globe and the injection through the inferior conjunctiva. The needle
is made behind the globe outside the muscle is at first directed backwards under the globe.
cone. The contents of the muscle cone include After it passes the equator, it is directed upwards
optic nerve, oculomotor nerves containing both and medially so as to enter the muscle cone.
superior and inferior branches, abducent nerve, Retrobulbar injections are painful and patients
nasociliary nerve, ciliary ganglion and vessels. are often given sedation to prevent pain, anxiety
The needle is inserted through the conjunctiva and associated complications. The most common
in the inferotemporal quadrant keeping it as and serious complication of retrobulbar injection
far laterally as possible along the orbital floor. is retrobulbar hemorrhage. Optic atrophy can
Often an additional medial injection is needed to occur due to direct damage to optic nerve or nerve
achieve complete akinesia. The onset of action compression due to injection of drug solution
after peribulbar block is slower than retrobulbar inside the meningeal covering of the nerve. Other
block but the risk of damaging the structures complications include stimulation of oculocardiac
inside the muscle cone is low. The risk of globe reflex, puncture of globe, inadvertent intravascular
penetration is also low. As compared to sub- and subdural injection and brain stem anesthesia.
In a series of 6000 retrobulbar blocks, 16 cases of drug solution affect the possibility of endothelial
apparent central spread of local anesthesia were cell toxicity. Solutions for intraocular injections
reported of which 8 developed respiratory arrest.31 are preservative free and, therefore, preservative-
Retrobulbar block has also been shown to reduce induced toxicity is not a concern.
blood flow in retrobulbar vessels and, therefore,
is avoided in patients with poor ocular perfusion Intravitreal
and glaucoma.32 Other routes of administration
such as peribulbar, sub-Tenon’s and topical have For intravitreal administration, drug solutions are
now largely replaced retrobulbar route because of injected directly into the vitreous humor. This
its potentially serious adverse effects. route of drug administration provides high drug
concentration in the posterior segment of eye
and is used in the treatment of conditions like
Intraocular endophthalmitis, age-related macular edema and
Intraocular routes of drug administration, require diabetic retinopathy. The medications can also be
drug administration inside the globe. The drugs delivered intravitreally in the form of implants that
can be injected in the anterior chamber, i.e. the provide sustained drug delivery over a prolonged
intracameral route or into the vitreous chamber, period. This route of administration is especially
i.e. the intravitreal route. useful for posterior segment drug delivery as other
routes of administration provide insufficient drug
Intracameral concentration in posterior segment. Evaluation
of an intravitreal fluocinolone acetonide implant
Several medications are administered by versus standard systemic therapy in noninfectious
intracameral route such as for pupillary dilatation posterior uveitis involving 140 patients showed
and anesthesia for surgical procedures, prevention that intravitreal implant provided better control of
of intraocular infection and inflammation. inflammation as compared to systemic therapy.34
The method provides immediate and easy Similarly for the treatment of endophthalmitis,
delivery of required concentration of drug into intravitreal administration of antibiotics is
the aqueous humor and, therefore, provides commonly practiced.
high efficacy. Moreover, the need for repeated
administration, as is necessary if using topical
Systemic
route, is avoided, which is especially a concern
in non-compliant patients. The corneal surface Systemic routes of drug administration for
toxicity associated with topical application is intraocular drug delivery include oral and
also avoided. Intracameral administration of parenteral routes. Orally administered drugs
medications, however, predisposes to toxic require absorption from the gastrointestinal tract
anterior segment syndrome (TASS). TASS into general circulation before the drug is delivered
is a general term that describes the sterile to the ocular tissue. Although a convenient method
postoperative inflammation due to non-infectious for drug administration, this route suffers from
causes such as intracameral medications. Presence several disadvantages such as slow onset of
of free radicals in the intracameral solutions action, poor absorption of highly polar drugs from
seems to contribute to endothelial toxicity leading gastrointestinal mucosa, destruction by enzymes
to corneal edema. In one of the studies, the free in gut, first-pass metabolism, uncooperative/
radical concentration equal to or higher than 0.5% unconscious patients or patients suffering from
hydrogen peroxide was detected in cefuroxime gastrointestinal conditions like vomiting, diarrhea
(0.61 mmol/L), 2% undiluted lidocaine (0.34 or other pathologies. Even if the sufficient
mmol/L) and bevacizumab (0.59 mmol/L).33 The amount of drug is absorbed into the systemic
drug concentration, pH and osmolarity of the circulation it may not be able to penetrate into
the ocular tissue due to blood ocular barrier. 9. Baum J. Treatment of bacterial ulcers of cornea
Intramuscular injections are made into the deltoid in the rabbit: a comparison of administration by
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10. Stern GA, Driebe. The effect of fortified anti
vein. The parenteral injections require aseptic
biotic therapy on the visual outcome of severe
conditions, may be painful and besides causing
bacterial corneal ulcer. Cornea. 1982;1:341.
local complications expose the body to high 11. Friedman SM, Margo CE. Topical gel vs
concentrations of drugs. Parenterally administered subconjunctival lidocaine for intravitreous
drugs have to pass through the blood-ocular injection: a randomized clinical trial. Am J
barriers and, therefore, may not reach in sufficient Ophthalmol. 2006;142(5):887–8.
concentration in the eye but the risk of systemic 12. Rocher N, Behar-Cohen F, Pournaras JAC, Naud
adverse effects increases. MC, Jeanny JC, Jonet L, et al. Effects of rat anti-
VEGF antibody in a rat model of corneal graft
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single sub-Tenon injection. Br J Ophthalmol. 28. Chew EY, Glassman AR, Beck RW, Bressler
2010; 94(5):654–8. NM, Fish GE, Ferris FL, et al. Ocular side
21. Cardillo JA, Melo LAS Jr, Costa RA, Skaf M, effects associated with peribulbar injections of
Belfort R Jr, Souza-Filho AA, et al. Comparison of triamcinolone acetonide for diabetic macular
intravitreal versus posterior sub-Tenon’s capsule edema. Retina–2011;31(2):284–9.
injection of triamcinolone acetonide for diffuse 29. Bordaberry M, Marques DL, Pereira-Lima JC,
diabetic macular edema. Ophthalmology. 2005; Marcon IM, Schmid H. Repeated peribulbar
112(9):1557–63. injections of triamcinolone acetonide: a successful
22. Ozdek S, Deren YT, Gurelik G, Hasanreisoglu B. and safe treatment for moderate to severe Graves’
Posterior sub-Tenon triamcinolone, intravitreal ophthalmopathy. Acta Ophthalmol. 2009;
triamcinolone and grid laser photocoagulation 87(1):58–64.
for the treatment of macular edema in branch 30. Mahfouz AKM, Al Katheri HM. Randomized
retinal vein occlusion.Ophthalmic Res. 2008; trial of superficial Peribulbar compared with
conventional peribulbar anesthesia for cataract
40(1):26–31.
extraction. Clin Opthalmol. 2007:1(1) 55–60.
23. Shimura M, Yasuda K, Nakazawa T, Shiono
31. Nicoll JMV, Acharya PA, Ahlen K, Baguneid S,
T, Sakamoto T, Nishida K. Drug reflux during
Edge KR. Central nervous system complications
posterior sub-Tenon infusion of triamcinolone
after 6000 retrobulbar blocks. Anesth Analg.
acetonide in diffuse diabetic macular edema not
1987; 66(12):1298–302.
only brings insufficient reduction but also causes
32. Huber KK, Remky A. Effect of retrobulbar
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Clin Exp Ophthalmol. 2009;247(7):907–12. haemodynamics. Br J Ophthalmol. 2005;
24. Shorr N, Seiff SR. Central retinal artery occlusion 89(6):719–23.
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for juvenile hemangioma. Ophthalmic Surg. P, Caslake M, Ramaesh K. Presence of free
1986;17(4):229–31. radicals in intracameral agents commonly used
25. Moshfeghi DM, Lowder CY, Roth DB, Kaiser during cataract surgery. Br J Ophthalmol. 2010;
PK. Retinal and choroidal vascular occlusion 94(12):1674–7.
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Am J Ophthalmol. 2002; 134(1):132–4. Usner DW, Fluocinolone Acetonide Study
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with regional ophthalmic anaesthesia in an acetonide implant versus standard systemic
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ChapteR 3
Ocular Pharmacokinetics
overview barriers. The major transport mechanisms that

help the drug molecules to pass across biological
Pharmacokinetics refers to the process of the barriers include:
uptake of drug by the body, the distribution of 1. Passive diffusion
drug to various tissues, its biotransformation and 2. Carrier-mediated transport
elimination from the body. The rate and extent to a. Facilitated diffusion
which the drug will reach its site of action and the c. Active transport
duration for which it will be available for action 3. Endocytosis
is determined by the pharmacokinetic processes.
Ocular pharmacokinetics is the study of changes
in drug concentration over time in the ocular tissue Passive Diffusion
when the drug is administered in various dosage Passive diffusion refers to the process of movement
forms by various routes according to various of drug molecules across the biological barrier along
regimens. Although the eye is an extremely its concentration gradient, i.e. from the site of higher
accessible organ for topical drug administration, concentration to the site of lower concentration
the ocular pharmacokinetic studies are extremely (Fig. 3.1). The process does not require energy
complex due to highly complex interplay of expenditure from biological system. Passive
multiple anatomical and physiological ocular diffusion is the primary mode of drug transport
barriers and physicochemical properties of the across the biological membranes including the
drug. The pharmacological actions, efficacy and ocular surface. Instillation of ophthalmic solution
possible toxicities depend upon the rate and extent into the cul-de-sac provides high drug concentration
to which the drug enters the ocular tissue. Ocular in the tear film creating a concentration gradient
pharmacokinetics involves the study of drug across the ocular surface. This facilitates the passive
absorption, distribution, metabolism and excretion. diffusion across the cornea and conjunctiva.
The aim of the ocular pharmacokinetic studies is
to understand the intraocular drug disposition and
provide a basis for rational use of ophthalmic drugs.
DRUG BIOTRANSPORT
During the movement from the site of admini
stration and from one body compartment to Figure 3.1 Passive diffusion through biological
another, the drug molecules cross the biological membrane
ocular pharmacokinetics 29
Besides concentration gradient, the passive dissociates and delivers the drug molecule to the
diffusion of drug molecules also depends upon other side. Thereafter, the carrier molecule moves
the ionization status and lipid solubility of the back to the surface for reuse.
drug. The nonionized and highly lipid soluble Facilitated diffusion refers to carrier mediated
drugs diffuse passively through the biological diffusion of molecules along the concentration
membranes at a rate that is proportional to their gradient, i.e. from higher to lower concentration
lipid:water partition coefficient, which means (Fig. 3.2). The process does not require energy
higher the lipid solubility, higher will be the expenditure. It is a capacity-limited process and
rate of diffusion. Most of the drugs are either the rate of diffusion depends on the ability of
weak acids or weak bases. Passive diffusion drug molecules to bind with the carrier and the
of these drugs depends on their degree of availability of carrier molecules. If two drugs
ionization, which in turn depends on the pH utilize the same carrier molecule for transport,
of the surrounding medium. According to the they will compete with each other for carrier
Henderson-Hasselbalch equation: binding and, therefore, will interfere with each
(Protonated) others absorption. Transport of glucose across
log = pKa − pH the corneal endothelium from aqueous humor to
(Unprotonated)
outer layers of cornea takes place by facilitated
The pKa of a drug is equal to the pH of diffusion.2
the medium at which half of the drug (50%) is Some drugs that are transported by facilitated
ionized. According to above equation, smaller diffusion include amino acids, antiviral drugs,
the pH relative to pKa, greater will be the anti-cancer drugs and vitamins like thiamine,
protonated form of the drug. For acidic drugs riboflavin and B12.
the protonated form is neutral and lipid soluble
Active transport refers to carrier mediated
but for basic drugs unprotonated form is neutral
transport of molecules against the concentration
and lipid soluble. Thus, weakly acidic drugs will
gradient and requires energy expenditure from
have better permeation at acidic pH and basic
biological system (Fig. 3.3). The required
drugs will have better permeation at alkaline
energy is generated by membrane ATPases and
pH. Most of the non-steroidal anti-inflammatory
accordingly, the process of active transport
drugs (NSAIDs) are weakly acidic and ionize
can be inhibited by inhibiting cell metabolism
at the pH of tears. Therefore, NSAIDs require
and reducing ATP levels by agents like sodium
formulation in an acidic solution so that the drug
cyanide. Like facilitated diffusion, it is a capacity-
can be predominantly in nonionized form and
limited process and depends upon the ability
can be better absorbed. Such acidic solutions can
of drug to bind with the carrier, availability
be irritant to ocular surface and are, therefore,
formulated using exicipients that can reduce the
irritating potential of the solution and stabilize
the drug.1
Carrier-mediated Transport
The polar compounds like amino acids, sugars and
some drug molecules are transported across the
biological barriers by carrier mediated transport.
The process utilizes a carrier molecule present
on the surface of the membrane, which forms
a complex with the drug molecule. The drug- Figure 3.2 Facilitated diffusion through biological
carrier complex moves through the membrane, membrane
inner less lipophilic endothelium. The relative
thicknesses of epithelium, stroma and endothelium
are approximately 0.1:1.0:0.01. The corneal
epithelium consists of a basal layer of columnar
cells, 2–3 layers of wing cells and 1–2 outermost
layers of squamous cells (Fig. 3.4).
Squamous cells in the outermost layer of
corneal epithelium are surrounded by tight
junctions (zonula occludens).The intercellular
spaces between wing cells and basal cells are
Figure 3.3 Active transport through biological membrane
comparatively larger. The tight junctions in the
most superficial layer of corneal epithelium
of carrier molecules and presence of other
serve as selective barrier for the small molecules
substrates that utilize the same carrier. Presence
and completely prevent the diffusion of
of several transporter molecules involved in active
macromolecules. The permeability of tight
transport such as amino acid transporters has been
junctions depends not only on its structural
demonstrated in corneal epithelium.3
integrity but also on the integrity of cytoskeleton
of epithelial cells. High extracellular and low
Endocytosis intracellular calcium levels are required for
The process of uptake of drug molecules by maintaining the normal permeability of tight
plasma membrane derived vesicles is known junctions. Hypertonic solutions have been shown
as the endocytosis. When the cell engulfs the to increase the leakiness of tight junctions. 5
fluid or drug in solution, the process is known as The pore size of the apical epithelium (< 3 nm)
pinocytosis. If the material engulfed by the cell allows small hydrophilic molecules like glycerol
is a particulate matter the process is known as (1.2 nm) to penetrate through the tight junctions
phagocytosis. The involvement of endocytosis but larger molecules like inulin (3 nm) fail to pass
for the transport of macromolecules has been through the corneal epithelium.6,7
demonstrated in cornea.4 The stroma, which forms 90% of the corneal
thickness, is hydrophilic in nature. It is relatively
hypocellular and consists of large volume of tissue
DRUG ABSORPTION fluid. The cellular components of stroma are mainly
the corneal fibroblast making about 2–3% of the
Topical Route total volume of stroma. The bundles of collagen
Following topical administration, the process fibrils in stroma have a regular arrangement.
of drug absorption into the ocular tissue is Because of the relatively open structure of stroma
quite complex. Primary routes of drug delivery particles up to the molecular weight of 500,000 kd
following topical administration of ocular drugs can pass through it.8 It is a rate limiting barrier
include cornea and conjunctiva. to small highly lipophilic molecules due to its
hydrophilic nature but allows easy passage to the
hydrophilic molecules. Because of the large fluid
Transcorneal Drug Absorption
volume, the stroma also acts as a reservoir for drugs
Cornea is the major site of drug absorption into that gain entry through the epithelium (Fig. 3.5).
the intraocular tissue for topically applied drugs. The endothelium, which forms the innermost
Cornea is a trilaminate structure consisting of layer of cornea is a single layer of hexagonal
an outer lipophilic epithelium and Bowman’s cells. It offers little resistance for the passage
membrane, middle hydrophilic stroma and of drug molecules due to the presence of gap
Figure 3.4 Corneal epithelium
Figure 3.5 Corneal stroma and endothelium
junctions and easily pumps out the tissue fluid drug molecules pass through the epithelium easily,
from stroma into the aqueous humor. they must possess adequate hydrophilicity as well,
Due to its biphasic solubility characteristics, to facilitate passage through stroma. Accordingly,
cornea functions as a barrier as well as depot for the drugs with very high lipophilicity have poor
the topically applied drugs.9 Most of the drugs penetration through cornea as compared to those
diffuse through corneal epithelium through with intermediate lipophilicity. 3 For corneal
transcellular (intracellular) pathways but some absorption of drugs, optimal partition coefficient
through the paracellular (intercellular) pathway has been reported to be 10–100 (1–10 on log
(Fig. 3.6). Lipophilic drugs traverse the corneal scale). As most of the drugs penetrate the cornea
epithelium through transcellular pathway but via transcellular pathway, along with other factors,
great resistance is offered for the diffusion of lipophilicity, pKa of the drug and the molecular
hydrophilic molecules, which can diffuse only size and shape also affect the transcorneal drug
through tight junctions in paracellular pathways. absorption.
Passive diffusion along the concentration gradient Besides the passive diffusion various active
is the main permeation mechanism for most transport mechanisms have also been identified
topically applied drugs by both the para- and in corneal epithelium, which are important
transcellular routes. Although, small lipophilic in maintaining the normal stromal hydration.
1. Bulbar conjunctiva, which is continuous with
the corneal epithelium.
2. Forniceal conjunctiva, which lines the fornices.
3. Palpebral conjunctiva, which is continuous
with the epidermis of eyelids.
The conjunctiva consists of stratified columnar
epithelium and lamina propria. The cells in the
superficial layer of epithelium have tight junctions
and this layer forms the main barrier for drug
penetration (Fig. 3.7).
Figure 3.6 Paracellular and transcellular drug
permeation Lipophilic drugs can diffuse through the
transcellular pathway but hydrophilic drugs
Although, evidence suggests that L-lysin and require passage through paracellular pathway. As
some peptides are actively transported by Na+K+- the hydrophilic drugs have to pass through the tight
ATPase in corneal epithelium, significant role of junctions in the paracellular pathways, the surface
active transport in transcorneal drug absorption area available for these drugs is significantly less
has not been identified. It may be of importance than that available for lipophilic drugs, which pass
for the transport of hypdrophilic molecules. through the transcellular pathway. Peptides and
Endocytosis has been suggested as another protein drugs that are hydrophilic pass through
possible mechanism for intracellular penetration this pathway and for macromolecules the passage
of large drug molecules. through the pores in tight junctions is the rate-
The extent of corneal permeability can be limiting step. However, the intercellular spaces
estimated by corneal permeability coefficient, in conjunctival epithelium are larger than those
which is calculated as follows: in corneal epithelium. Therefore, conjunctival
Corneal permeability coefficient (cm/sec) = permeability to hydrophilic drugs is higher than
that of corneal permeability and molecules up
Corneal flux
to the molecular weight of 20000–40000 kd can
Initial drug concentration x corneal surface area pass through the conjunctiva.11-13 Accordingly,
The corneal flux can be calculated from the mannitol has 55 times higher conjunctival
slope of regression line obtained from the linear permeability as compared to corneal permeability.
The ocular availability of peptide molecules
part of the curve plotted between the amount
through conjunctiva is limited not only due to
permeated versus time.10 For a large number
large molecular size but also due to degradation
of ophthalmic drugs the corneal permeability
by enzymes secreted by conjunctiva. Presence of
coefficient varies from 0.44 × 10-6 to 78.8 × 10-6
carrier-mediated mechanisms in the conjunctival
cm/sec. Value less than 10 × 10-6 cm/sec indicate
epithelium has also been suggested to play an
poor corneal permeability. Corneal permeability
important role in transferring drug molecules to
of a drug can be modified by a number of factors,
the interior of the eye.
which are discussed in the following section.
Due to its high vascularity, conjunctiva is also
a major route for the entry of topically applied
Transconjunctival Absorption drugs into the systemic circulation. Some drugs
Conjunctiva is a membrane of connective tissue such as timolol and nipradilol have significantly
that covers most of the ocular surface. It is a higher conjunctival permeability coefficient as
thin vascularised mucus membrane that plays an compared to corneal permeability coefficient.
important role in the formation and maintenance Moreover, the surface area of conjunctiva (16–
of precorneal tear film. The conjunctiva is divided 18 cm2) is significantly larger than that of cornea
into three parts: (1 cm2).14 Therefore, due to higher permeability,
Figure 3.7 Conjunctival epithelium
high vascularity and large surface area, charge (ionized) at physiological pH and hence
conjunctiva is a major route of systemic drug hydrophilic, penetrate poorly as compared to
absorption following topical instillation.15 those with no net charge (non-ionized) and
hence lipophilic. Lipophilicilty enhances drug
Transscleral Absorption permeation through transcellular route. The
degree of ionization of weak acids and bases
Sclera, the tissue lying immediately underneath depends upon the pH of the medium. Timolol
the conjunctiva, is much more permeable to (weak base, pKa 9.2) is poorly ionized at higher
larger molecules than conjunctiva or cornea.16 pH of the instilled solution (6.2–7.5) and,
The sclera has three layers—episclera, stroma and therefore, has greater ocular tissue concentration
lamina fusca. It consists of mucopolysaccharides at this pH as compared to lower pH solutions.17
and bundles of collagen fibrils. Topically Flurbiprofen, an acidic drug, has shown reduced
applied drugs permeate easily through sclera corneal permeability at higher pH.18
by passing into perivascular spaces, through Besides the degree of ionization, the charge on
the gel-like mucopolysacchardises and through the molecule also affects its corneal permeation.
spaces between collagen network. For the Above its isoelectric point (pI 3.2) the corneal
subconjunctivally injected drugs, the physical epithelium is negatively charged.19 Consequently,
and biological barrier of conjunctiva and cornea cations penetrate through cornea more easily as
is circumvented and higher intraocular drug compared to anions. If the pH of the solution is
concentrations are achieved. below pI, cornea is more permeable to anions,
however, at this pH the solution is too acidic for
Factors Affecting Ocular Absorption of clinical use. Therefore, negatively charged drug
molecules penetrate cornea poorly as compared
Topically Administered Drugs to positively charged molecules.
1. Physicochemical characteristics of The ocular tissue including cornea consists of
significant levels of enzymes such as esterases,
drug which metabolize drugs during and after
The ionic characteristics of drug molecules in absorption. 20 Presence of cytochrome P450
water greatly influence the drug absorption. The enzymes has also been demonstrated in cornea.21
drug molecules with net positive or negative Consequently, drugs are likely to be destroyed
by these enzymes causing reduced therapeutic The pH of the vehicle and buffers used in
efficacy. Some of the drugs are prodrugs and the formulation are other important factors
following metabolism are converted to active influencing ocular absorption by affecting
drug molecules. The drugs like dipivefrin the ionization of drug molecules. The pH of
(lipophilic) have been designed to facilitate the formulation is adjusted in such a way that
corneal permeation. Once absorbed through unionized form of drug predominates and easy
the cornea it is metabolized to active molecule, ocular penetration is permitted. An optimal pH
epinephrine, which is more hydrophilic. of the formulation is also necessary to ensure
physical and chemical stability of drug as well as
2. Composition of drug formulation other ingredients and for ocular comfort.
The tonicity of ophthalmic solution for
Most of the ophthalmic drugs are formulated topical use is adjusted in such a way that it is
either as solutions or suspensions. Solutions approximately isotonic to tears. Eye can tolerate
are clear liquids in which all the ingredients a wide range of tonicity between 266–445 mOsm/
are completely soluble and there is minimal kg without causing any pain or discomfort.
interference with vision. Although, the drug Ophthalmic preparation with excessive tonicity
molecules in solutions are immediately available cause stinging pain on instillation and induce
for absorption, there is equally rapid drainage reflex tearing. Tearing dilutes the drug solution
out of cul-de-sac. Ophthalmic suspensions and reduces its extent of absorption.
contain micronized drug molecules (< 10 μm in Increased viscosity of the solution allows
diameter) of relatively low aqueous solubility the drug to stay in contact with ocular surface
dispersed in liquid vehicle, such as prednisolone for a longer time, thereby increasing the drug
acetate. The small drug particles stay in cul-de- absorption. This factor is further discussed in the
sac longer than those of solution, thus prolonging next section.
the drug’s availability for absorption.22 The drug Multi-dose containers of ophthalmic prepar
delivery from suspension takes place in two ations usually contain a preservative to prevent
phases. The first phase of rapid delivery and growth of microorganisms. Preservatives in
second phase of slow delivery from retained ophthalmic solutions such as benzalkonium
particles. chloride enhance the ocular absorption of drugs
In general, small particle size favors faster and can be toxic to ocular surface.23
dissolution and faster absorption. But in case of
suspensions small particle size will favor the easier 3. Residence time on ocular surface
drainage out of the cul-de-sac thus reducing the
retention time and consequently the net absorption. The capacity of conjunctival sac is approximately
Suspensions require adequate shaking of the 15–30 μL and the natural tear film volume is 7–8
container before administration because of the μL. At a normal blink rate of 15–20 blinks/min, tear
sedimentation of particles. The rate of sedimentation turn over rate is approximately 16% per minute but
depends on particle size. The larger the particles, is greatly influenced by environmental temperature
faster the rate of sedimentation and lower the rate of and humidity. Most of the ophthalmic solution
resuspension. Larger particles in suspension cause applicators deliver the solution in a volume of
more ocular irritation, tearing and drug loss by about 50–100 μL, therefore, a significant portion of
drainage. Particle size <10 μm generally minimizes the solution is lost due to overspill. The remaining
ocular irritation, however, this is not a clear-cut limit is subjected to drainage through the nasolacrimal
because other factors such as particle shape, density duct until the normal tear volume is restored. Once
and concentration can influence the degree of ocular the normal tear volume is restored further tear
irritation and drug loss. turnover dilutes the drug solution and reduces the
concentration gradient across the ocular surface. methylcellulose, polyvinyl alcohol or guar
With spontaneous tear flow, the instilled drug gum. 24-26 Optimal viscosity suggested for
completely disappears from cul-de-sac in about 5 ophthalmic solution is 12–15 cp (centipoise).
minutes and 80% of the applied drug is lost through The preparations with higher viscosity do not
nasolacrimal drainage (Flowchart 3.1). allow easy mixing with aqueous phase in the
Following instillation of drug solution, eye, cause distortion of optical surface leading
lacrimation and blinking significantly influence to blurred vision. High viscosity solutions cause
the residence time of the drug on the ocular ocular irritation, reflex blinking lacrimation and
surface. Reflex tearing following instillation of drug loss due to increased drainage. Formulations
an irritant drug causes increased rate of drug loss. with viscosity higher than 30 cp are very sticky
Similarly, physical, psychological and emotional and uncomfortable for use.
stress causes increased tearing and hence the
higher drug loss. Lid closure, topical and general 4. Integrity of precorneal tear film and
anesthesia reduce the rate of tear flow, thereby, ocular surface
reducing the drug loss. Blinking movements
promote drainage of instilled drug through the The topically applied ophthalmic drug mixes with
nasolacrimal duct and each blinking movement the precorneal tear film before getting absorbed
removes about 2 μL of fluid from the cul-de-sac. through the ocular surface. The pH of normal tear
Besides drug loss due to nasolacrimal drainage, a fluid ranges from 6.5 to 7.6. If the pH of instilled
number of other factors such as tear evaporation, medication is not within physiological limits,
drug deposition on lid margins, drug binding increased tear turnover and to some extent the
to proteins in tears and drug metabolism by buffering system of tears brings its pH within
enzymes in tears also reduce the amount of physiological range. Any change in the pH of tear
drug absorption. Instillation of multiple drops of film will affect the ionization of drug and hence
different medications in quick succession causes its capacity to diffuse and get absorbed through
substantial loss by washout. If the second drop is the ocular surface.
applied about 5-minutes after the first, almost no Precorneal tear film consists of an outer layer
washout effect occurs on the first drop. of mixed lipids, middle aqueous layer containing
Increasing the residence time of ophthalmic proteins and deeper mucin layer of glycoproteins.
solution onto the ocular surface increases The deeper mucin layer is extremely important for
the amount of drug absorption. The measure the stability of tear film and promotes adherence of
that is commonly adopted for this purpose tear film to the lipophilic epithelium of cornea and
is by changing the vehicle of the solution conjunctiva. Any alteration in the composition of
to more viscous consistency by adding tear film causes instability of tear film and reduces
viscoelastic substances such as hydroxypropyl drug’s residence time on ocular surface.
Flow chart 3.1 Fate of topically administered drugs

As discussed earlier an intact corneal and Systemic Route
conjunctival epithelium form the most significant
barrier to drug absorption from ocular surface. Any Drugs can also be administered systemically
damage to corneal and conjunctival epithelium for the treatment of ophthalmic diseases. The
due to disease, trauma or toxins significantly systemic routes include the oral and parenteral
damages this barrier causing enhanced absorption routes.
of drugs from the ocular surface.
Oral
5. Extent of systemic absorption Orally administered drugs are mainly absorbed
The drug remaining in contact with ocular surface through gastrointestinal mucosa by passive
is available for absorption through the ocular diffusion. The mucosa of gastrointestinal tract is
surface into the ocular tissue. However, following more permeable to lipid soluble and nonionized
topical application, significant amount may get forms of drug and less permeable to ionized
absorbed into the systemic circulation by and hydrophilic drugs. Sugars, amino acids and
1. Getting absorbed through nasal and other nutrients are absorbed by active transport.
nasopharyngeal mucosa following drainage Following absorption from gastrointestinal tract,
through nasolacrimal duct. drug molecules enter the portal circulation and
2. Getting absorbed through highly vascular reach liver prior to their entry into the systemic
conjunctiva and lid margins. circulation. During the passage through the gut
Normally, the topically administered wall and liver drug may undergo metabolism
formulations are rapidly drained through open and this will affect the amount of drug entering
punctum into the nasolacrimal duct, followed the systemic circulation in its unchanged
by absorption through the lining mucosa. Since, form. Presence of efflux transporters such as
the punctal patency requires open lids, systemic P-glycoproteins in the enterocytes also interferes
absorption of the topically administered drugs can with the drug absorption. Inadequate drug
be restricted by gently closing the eyes for about
absorption may sometimes be due to diseased
1 minute. The measure has been shown to greatly
condition of the gastrointestinal tract, vomiting
improve the efficacy of topically administered
or diarrhea.
drugs. In the same way, applying gentle pressure
The metabolism that the drug undergoes
over puncta for about 5 minutes also restricts
during its first passage through the gastrointestinal
drainage of drug into the nasolacrimal duct and
tract before entering the general circulation is
increases ocular absorption.
termed as “first-pass metabolism” (Flowchart
Conjunctival vasculature is an important route
3.2). Greater the extent of first-pass metabolism,
for systemic absorption of topical drugs, which
lesser the amount of unchanged drug that enters
cannot be blocked by lid closure and punctual
the circulation.
pressure. Instillation of multiple drops at a time
does not increase the ocular bioavailability
but increases the risk of adverse effects due Parenteral
to enhanced systemic absorption. Reducing Drug absorption following subcutaneous and
the volume and increasing the viscosity of intramuscular injection usually occurs by passive
eyedrops, controlling drug release from depot diffusion from the injection site to plasma or
preparations, prodrug-derivatization, and addition lymph. As the muscles are more vascular than
of vasoconstrictive agents can minimize the subcutaneous tissue, drugs are more rapidly
systemic drug absorption.27 absorbed after intramuscular injections as
Flow chart 3.2 Systemic drug absorption by various routes
compared to subcutaneous. When administered transparency of intraocular fluids. But the BAB is
by intravenous route, the total amount injected is not absolutely impermeable to proteins and allows
immediately available in circulation. small amount of proteins to enter aqueous humor
in normal eye, which contains soluble proteins
Ocular Drug Absorption Following equivalent to approximately 1% of plasma level.
Systemic Administration BAB has been shown to consist of several efflux
and uptake transporters, which provide additional
Following systemic drug administration, plasma pathways for drug elimination from the aqueous
concentration versus time profile usually translates humor and vice versa.28,29
into concentration versus time profile at the site BRB is located in the posterior part of eye and
of disease. But eye is a privileged site like brain consists of an outer retinal pigment epithelium and
where the concentration-time profile may differ endothelium of retinal capillaries. The endothelial
significantly from that of plasma because of the cells in retinal capillaries have tight junctions
existence of blood-ocular barriers. The blood made up of bands of zonula occludens. Because of
ocular barriers that include blood-aqueous (BAB) the narrow tight junctions, passage to hydrophilic
and blood-retinal barriers (BRB) tightly control substances through paracellular pathways is
the chemical environment of the ocular tissue. highly restricted. There is absence of fenestrae
These barriers also play an important role in and pinocytotic activity in the endothelial cells
eliminating the metabolic end products from the further contributing to the restricted permeability.
ocular tissue. The outer retinal pigment epithelium is the first
BAB is located in the anterior part of eye barrier for the drugs that try to gain entry into
in the ciliary body and iris. The ciliary body the eye from systemic circulation. The adjacent
plays more important role as it is located where pigmented epithelial cells are joined by extensive
the aqueous and vitreous meet. It has large zonulae occludentes, which seal the intercellular
surface area covered by ciliary processes and is spaces in pigment epithelium just like vascular
equipped with multiple transport mechanisms. endothelium. The cells in the BRB are known to
BAB is formed by capillary endothelial cells consist of a variety of enzymes such as angiotensin
and nonpigmented ciliary epithelium. These converting enzyme, monoamine oxidase,
layers do not allow passage of plasma proteins pseudocholinesterase, dopa decarboxylase etc.,
into the aqueous humor that would impair the which make up a metabolic barrier. Several efflux
osmotic and chemical equilibrium and hence the and uptake transporter molecules are expressed
in BRB.3,29 Penetration of drugs through BRB (AUC) indicates the drug’s bioavailability. Both
after systemic administration is often poor and the rate and extent of absorption influence the
to achieve therapeutic concentrations in posterior clinical outcome (Fig. 3.8).
segment of eye, drugs are injected intravitreally. A Ocular and systemic bioavailability refer to the
number of methods have been described to alter rate and extent to which the drug is available at the
the permeability of BRB and hence allow the site of action within the ocular tissue or systemic
penetration of drugs from systemic circulation circulation respectively. Ocular bioavailability
into the posterior segment of eye. Intracarotid of topically administered drugs is generally an
infusion of hypertonic saline solution has been estimate of the amount of drug absorbed into the
shown to cause increased BRB permeability due ocular tissue compared to the amount of drug
to shrinkage of endothelial cells and opening of administered. It is estimated that generally 5% or
tight junctions.30 However, this opening is non- less of the topically administered drug penetrates
specific and is associated with ocular and CNS the ocular surface and reaches the interior of the eye.
side-effects. Exposure to white and blue light has The total volume of the anterior and posterior
been shown to increase the BRB permeability chamber of the eye containing 200–300 µL of
by promoting vesicular uptake. 31 Chemical aqueous humor, is generally considered the
modification of drug molecules to make them central chamber into which the instilled drug
more lipophilic will allow better penetration enters following absorption through ocular
through intracellular pathways. Drug molecules surface barriers. The aqueous humor drug
can also be modified in such a way that they concentration versus time curve is often used to
resemble endogenous ligands and, therefore, estimate the ocular bioavailability of topically
can utilize the same carrier-mediated transport administered drugs. However, the bioavailability
mechanisms for uptake into the ocular tissue. can also be estimated in other parts of eye such as
Liposome encapsulated drugs have also been cornea, uvea, vitreous, retina by measuring drug
used to enhance permeability through BRB. concentrations in the corresponding tissue over
For targeted delivery of drugs into the retina time and calculating the AUC.
another approach utilizes coupling of drugs with The ocular bioavailability increases with
antibodies that are directed against epitopes increased drug diffusion across cornea such as in
present on endothelial cell surface. Such an cases of corneal ulcer when the epithelial barrier
approach allows selective transport through is destroyed. Increased partition coefficient also
retina.32 increases the ocular bioavailability and this can
be achieved by increasing the drug’s lipophilicity.
Increased rate of drug elimination from tears
BIOAVAILABILITY and aqueous humor decreases aqueous drug
Bioavailability is defined as the fraction of
unchanged drug reaching the site of action
following administration by any route. It is a
measure of the rate as well as the extent to which
the drug is available at the site of action after
administration. Bioavailability of a drug after
administration by a particular route is commonly
measured by calculating the area under the
concentration versus time curve. The peak
concentration (Cmax) and the time required to reach
the Cmax (tmax) are the indicators of the extent and
rate of absorption respectively. Area under curve Figure 3.8 Concentration versus time curve
concentration. The drug elimination from tear topical application as the drug diffuses slowly
film can be reduced by increasing the solution’s through lens and vitreous and at the same
residence time on ocular surface. The drug time undergoes elimination with aqueous
elimination from aqueous humor depends upon humor turnover, metabolism and systemic
the aqueous turnover, which can be affected by absorption. Therefore, to achieve therapeutic
the drugs like antiglaucoma medications. concentrations in the posterior parts of eye,
Systemic bioavailability is determined by subconjunctival and intravitreal injections are
the AUC of the plasma concentration versus used. Drugs injected intravitreally, provide high
time curve. Since the bioavailability of intra drug concentration in the posterior segment and
venously administered drugs is 100%, the diffuse predominantly to the posterior aqueous
bioavailability by other routes of administration chamber due to the absence of a limiting
is calculated by a comparison with AUC after membrane anteriorly. From the vitreous drugs
intravenous administration. However, for the can also diffuse through lens or retina-choroid-
drugs administered systemically for ophthalmic scleral membrane.
diseases, the plasma drug concentration may not Systemically administered drugs enter the
be a true representation of ocular bioavailability ocular tissue after passing through blood ocular
due to the presence of blood ocular barriers. barriers and follow the similar distribution
The bioavailability of systemically administered pathway as described above. Generally, after
drugs is affected by physicochemical properties systemic administration, lipophilic drugs penetrate
of the drug, route and site of administration, better into the ocular tissue. Extensive plasma
gastric emptying and intestinal motility, protein binding of drugs limits their penetration
coadministration with food and other drugs, through the blood-ocular barriers.
diseases of gastrointestinal tract, extent of first-
pass metabolism and genetic polymorphism. Volume of Distribution (Vd)
After absorption into the central ocular
OCULAR DRUG DISTRIBUTION compartment, the drugs are distributed to various
parts of ocular tissue. In the simplest form, the eye
For topically administered drugs, absorption of can be considered as a single compartment into
hydrophilic drugs is better through conjunctival- which the total quantity of absorbed drug gets
scleral route. The hydrophilic drugs absorbed distributed. The apparent volume of distribution
through this route are deposited in the ciliary (Vd) is the parameter used to indicate the extent
body whereas the lipophilic drugs are absorbed of drug distribution. It is defined as the apparent
through cornea, diffuse through pupil and pass volume required to distribute a known amount
against the aqueous flow into the posterior of drug at the concentration observed in central
chamber. Diffusion of drugs from aqueous ocular compartment (anterior chamber). For drugs
humor to lens, vitreous and retina is slow and, injected intravitreally, the vitreous humor forms
therefore, immediately following absorption the central compartment. Accordingly, Vd can be
the aqueous humor levels of drug may be high. represented as follows:
However, as the drug distributes to other parts Apparent volume of distribution (Vd) =
of ocular tissue, the aqueous levels reduce. Total amount of drug adsorbed
Usually following topical instillation, high
Aqueous humor drug concentration
drug concentration is achieved in anterior
compartments, i.e. cornea, conjunctiva, sclera, Figure 3.9 illustrates the relationship of
uvea and aqueous. Distribution to the posterior drug concentration, Vd and the extent of drug
ocular compartments is often poor after distribution.
Figure 3.9 Apparent volume of distribution
Accordingly, considering the eye as a single Free drug (unbound) + protein ↔ Drug-
compartment following absorption of equal protein complex (bound)
amount of drug, smaller aqueous humor drug Drug when complexed with proteins is
concentration indicates a larger tissue distribution
inactive and only the free form of the drug is
of drug. But a relatively larger aqueous humor
pharmacologically active. It is the free form of
drug concentration indicates smaller tissue
the drug that can diffuse from one to another
distribution of drug.
compartment to maintain equilibrium and can get
The eye, however, is not a single compartment
metabolized and excreted. As the unbound drug is
and consists of multiple sub-compartments such
metabolized and excreted, more is released from
as tear film, cornea, conjunctiva, sclera, uvea,
aqueous, lens, vitreous and retina. Although, bound form to replace the lost amount. Extensive
the volume of aqueous humor is approximately protein binding increases the availability of drug
0.3 mL but the apparent volume of ocular drug over a prolonged period of time thus prolonging
distribution (Vd) is usually larger due to multi- its duration of action.
compartment distribution. The values of V d Binding to uveal pigment also affects the
typically vary from 0.24–0.64 mL, however, drug distribution especially for drugs that have
some drugs like ketorolac tromethamine (Vd = the site of action in ciliary body. For example,
1.93 mL) and levobunolol (Vd = 1.65 mL) have timolol will be required in comparatively higher
high values. doses to reduce intraocular pressure in people
with heavily pigmented iris due to significant
binding to uveal pigment. Some of the ocular
Effect of Protein and Pigment
compartments like uvea, lens and vitreous also
Binding on Drug Distribution act as drug reservoir. This may be responsible
Extensive binding of drugs to proteins in aqueous for increasing the aqueous humor half-life of
humor reduces their distribution to other parts of drugs by allowing diffusion of drug when its
eye. Binding of drugs with proteins is reversible level in aqueous humor is decreasing due to drug
and is in dynamic equilibrium, i.e. elimination. Drug accumulation in ciliary body
example, ketone reductase metabolizes the
Flowchart 3.3 Ocular drug distribution and elimination
antiglaucoma β-blocker, levobunolol, into an
active metabolite.35 Similarly, latanoprost is a
prodrug of PGF2α and dipivefrin for epinephrine.
Esterases are predominantly present in the iris-
ciliary body followed by cornea and aqueous
humor. The esterase activity in pigmented rabbits
was found to be higher than in albino rabbits.
Aminopeptidase activity is high in corneal
epithelium and iris-ciliary body.20 The activity
of ketone reductase was shown to be highest in
corneal epithelium followed by iris-ciliary body,
conjunctiva and lens.
Besides the metabolic breakdown, drug
elimination from ocular tissue also takes place by
aqueous humor turn over and systemic absorption.
Aqueous humor turn over is about 2–5 µL/min
following repeated topical instillation may also and amounts to 1–1.5% of the chamber volume/
be a cause of ocular toxicity (Flowchart 3.3).33 min.36,37 Intravitreally injected drugs are primarily
eliminated with aqueous humor turn over after
diffusing anteriorly or through the retina-choroid-
OCULAR DRUG ELIMINATION
scleral membrane.
Elimination of drugs to terminate their
action involves both the drug metabolism or Systemic Drug Metabolism and
drug biotransformation and excretion. Drug Excretion
biotransformation refers to the enzyme catalyzed
chemical transformation of drugs within the Absorption into the systemic circulation is the
biological system. For elimination of drugs from major route of drug elimination from the ocular
ocular tissue the three main pathways include: tissue. For drugs administered by ocular routes
aqueous humor turnover, drug metabolism in that enter the systemic circulation or systemically
ocular tissue and metabolism and excretion administered drugs, liver is the primary site of
following systemic drug absorption. metabolism. Other sites of drug biotransformation
include intestine, kidney, lungs, placenta, adrenal
Ocular Drug Metabolism and cortex and skin. Biotransformation leads to
conversion of a lipid soluble compound into water
Elimination
soluble compound, thus facilitating its excretion
Several enzymes that play important role in in urine. Drug biotransformation reactions are
ocular drug metabolism include esterases, grouped into two types:
ketone reductase, catechol-O-methyl transferase, Phase I reactions take place in microsomes,
monoamine oxidase, acid phosphatase, β-hydro involve microsomal enzymes and include
xylase, oxidoreductase, aminopeptidase, UDP- oxidation, reduction or hydrolysis. Microsomal
glucoronyl transferase, aryl amine acety enzymes involved are associated with smooth
ltransferase and aryl sulfatase. 20,34,35 These surfaced endoplasmic reticulum and include
enzymes metabolize the drugs and either mixed function oxidases and cytochrome P-450.
inactivate them or convert them into an active These enzymes are non-specific and can be
drug if the parent drug was a prodrug. For stimulated or inhibited by a number of drugs.
They metabolize only lipid soluble drugs. will increase and may lead to toxicity. For
Resultant metabolites are small polar or non-polar example, increased metabolism of paracetamol in
molecules, which may be active or inactive. alcoholics may precipitate hepatotoxicity due to
Phase II reactions are synthetic or conjugation paracetamol metabolite even at therapeutic doses.
reactions in which parent drugs or their Enzyme induction primarily takes place in liver
phase I metabolites conjugate with one of the but may occur at other sites such as lungs and
endogenous compounds leading to formation placenta. Enzyme induction is usually reversible
of the polar compounds such as glucuronide, and takes about 1–2 weeks to reach the peak
acetate, sulfate, riboside phosphates and methyl induction and about the same time to subside once
or glutathione derivatives. Except for the the inducer drug is withdrawn.
glucuronide conjugation, all other conjugation Repeated drug administration can also cause
reactions require non-microsomal enzymes. inhibition of metabolizing enzymes leading to
Non-microsomal enzymes are present in the accumulation of unmetabolized drug in circulation
mitochondria and cytoplasm of hepatic cells, and increased pharmacological response. Enzyme
and in plasma. Metabolites are water soluble inhibitors decrease the metabolism of not only
and inactive with the exception of morphine the inhibitor but also other drugs utilizing the
glucuronide, which is more potent than morphine. same enzyme, when co-administered. Enzyme
Some drugs can directly undergo phase II inhibition is usually reversible but occurs rapidly.
reactions without undergoing phase I reactions. Enzyme inhibition may involve non-specific
Various factors can affect the rate of hepatic mixed function oxidases or specific enzymes like
drug metabolism. Neonates and premature babies monoamine oxidase, xanthine oxidase, etc.
due to their immature hepatic enzyme system
may metabolize drugs at a slower rate. Elderly Drug Excretion
above the age of 60 also metabolize drugs
slower than the young adults due to reduced Drugs from systemic circulation are excreted
hepatic blood flow. Enzyme expression may either unchanged or in the form of their water
differ due to genetic polymorphism. Starvation soluble metabolites. Kidney is the major route of
leads to enzyme inhibition and a diet rich in drug excretion.
proteins enhances the rate of metabolism. Dietary Renal excretion of drugs involves three
deficiency of vitamins and micronutrients can processes: glomerular filtration, tubular
alter the rate of metabolism. Enzyme activity reabsorption and tubular secretion. Drugs that
also gets altered in diseases like hepatitis, cardiac have molecular size of less than 20,000 kd and
diseases, thyroid diseases, etc. are not extensively bound to plasma proteins,
undergo glomerular filtration. Rate of glomerular
filtration is also affected by renal perfusion.
Enzyme Induction and Inhibition Higher the renal perfusion, greater is filtration.
Repeated drug administration may lead to Glomerular filtration can remove about 20%
growth of smooth endoplasmic reticulum and of the drug from circulation. The rest reaches
enhanced microsomal enzyme activity. As a proximal tubules from where it is actively
result, the inducer drug is metabolized at a faster secreted in the tubular lumen utilizing energy
rate causing its reduced pharmacological effect. dependent carrier systems. High protein binding
Enzyme induction increases the metabolism of does not interfere with the tubular secretion but
not only the inducer drug but also other drugs helps in delivering the drug molecules at the
that utilize the same enzymes when administered sites of secretion. As the plasma concentration
concurrently. However, if the metabolite of falls, more drug dissociates from protein binding
inducer or the concurrently administered drug is sites and becomes available for secretion. There
an active compound the pharmacological response are two independent carrier systems, one for
acidic drugs like aspirin and penicillin and The constant 0.693 = log of 2. (As the drug
other for basic drugs like morphine. Both are elimination can be described by an exponential
nonspecific and, therefore, drugs utilizing same process, the time taken for a twofold decrease can
carrier molecule may compete with each other be shown to be proportional to log 2)
for tubular secretion causing drug interactions. k = elimination rate constant = fraction of the
Clinically significant drug interactions mainly total amount of drug removed from the tissue per
involve acidic drugs. For example, probenecid unit time and is expressed as
increases efficacy of penicillin by competing for k = Cl/Vd
tubular secretion and delaying its excretion. The t1/2 = 0.693 × Vd/Cl
combination is used in the treatment of various
infections. Following glomerular filtration and For the single compartment model of the eye,
tubular secretion drugs may get reabsorbed from the half-life is directly proportional to Vd and
tubular lumen. Reabsorption is largely by passive indirectly proportional to clearance. Half-life is
diffusion and, therefore, depends upon the lipid not an exact index of drug elimination, because
solubility, degree of ionization of drug and the pH it depends on Cl and V d, both of which may
of urine. Excretion of weakly acidic drugs may change independently. Half-life can not predict
be enhanced by making the urine pH alkaline the duration of action after single dose, which is
related more to distribution rather than clearance/
and excretion of weakly basic drugs increases
elimination. But it can predict the rate and extent
in acidic urine. Strongly acidic and basic drugs
of accumulation after repeated dose as well as the
remain ionized at all pH ranges and hence will
rate of wash out after the termination of treatment.
be excreted.
Half-life predicts the time required to reach the
steady state concentration following multiple dose
Clearance administration.
Clearance is one of the basic pharmacokinetic
parameter that indicates body’s ability to eliminate Kinetics of Elimination
the drug. It is defined as the theoretical volume
of tissue/tissue fluid from which the drug is First Order Kinetics
completely removed per unit time. Clearance of Majority of ophthalmic drugs follow first order
the drug predicts the rate of drug elimination in kinetic of elimination. For such drugs, a constant
relation to its concentration as shown below: fraction of drug is eliminated per unit time, i.e.
Rate of elimination 1 hour
Clearance (Cl) = 1 hour
Concentration 200 (mg/mL) → 100 (mg/mL) → 50 (mg/mL)
[50% is excreted per unit time]
Clearance can be calculated for individual
organ such as eye by dividing the rate of If the drug concentration increases such as due
elimination from eye by the concentration of to increased dose, the amount of drug excreted
drug reaching the eye. Total systemic clearance is also increases per unit time as is shown below:
equal to the sum total of clearance by all organs.
1 hour 1 hour
200 (mg/mL) → 100 (mg/mL) → 50 (g/mL)
Elimination Half-life [50% is excreted per unit time]
Elimination half-life (t1/2) is defined as the time
required to change the amount of drug in the tissue
1 hour 1 hour
by half. It is expressed as follows: 400 (mg/mL) → 200 (mg/mL) → 100 (mg/mL)
Plasma half life (t1/2) = 0.693/k [50% is excreted per unit time]
As is clear from the above example, increase Following repeated fixed dose administration
in drug concentration from 200 µg/mL to 400 µg/ at an interval equal to t1/2, it takes five t1/2 to
mL does not change t1/2 (50% of drug is excreted achieve 97% of its steady state concentration as is
in 1 hour at both concentrations). Therefore, for shown in Figure 3.11. At steady state, rate of drug
the drugs following 1st order kinetics – t1/2 remains absorption equals the rate of drug elimination,
constant because Vd and Cl do not change with thereby, maintains a constant drug concentration.
the dose. The ocular drug clearance for the drugs At steady state following fixed dose admini
following first order kinetics can be expressed stration at an interval of one t 1/2 , the drug
as follows: concentration fluctuates between peak and trough
concentrations as is shown in the Figure 3.11
Ocular drug clearance (µL/min) = elimination
(Table 3.1).
rate constant × ocular Vd.
Elimination rate constant is the fraction of the
Zero-order Kinetics
total amount of drug removed from the ocular
tissue. Some drugs undergo zero-order kinetics of
Concentration versus time curve for drugs elimination due to saturation of elimination
following first order kinetics is curvilinear but processes and for such drugs a constant amount
when plotted using log dose concentration it is (not constant fraction) of drug is eliminated per
a linear curve. First order elimination will allow unit time. Therefore, these drugs get eliminated
excretion of 97% of drug in 5 half-lives following at a rate independent of their concentration
single dose administration as is shown below meaning, thereby, an increase in concentration
(Fig. 3.10): will not proportionately increase the rate of
Doubling the dose will allow increase in elimination.
the duration of action by one t1/2. In the above
1 hour 1 hour
example if the efficacy of drug lasts until the 200 (mg/mL) → 100 (mg/mL) → Nil
concentration falls to 25 µg/mL, the duration of [100 mg is excreted per unit time].
action at a dose, which gives 100 µg/mL will last
for 2 hours. If the dose is doubled so that the initial
concentration is 200 µg/mL the duration of action 400 (mg/mL) → 300 (mg/mL) → 200 (mg/mL)
will last for 3 hours, i.e. increase by one t1/2. [100 mg is excreted per unit time].
Figure 3.10 Concentration versus time profile for drugs following first order kinetics
Figure 3.11 Steady-state concentration is achieved in 4–5 t1/2
Table 3.1 First versus zero order kinetics
First order kinetics Zero-order kinetics

•• Elimination processes are not saturated •• Elimination processes are saturated
•• A constant fraction of drug is eliminated per unit •• A constant amount of drug is eliminated per unit
time time
•• Amount of drug excreted per unit time increases •• Clearance decreases with increase in drug
with increase in drug concentration concentration
•• Clearance remains constant with increase in •• Amount of drug excreted per unit time remains
drug concentration unchanged with increase in drug concentration
•• Rise in drug concentration is linearly related to •• Rise in drug concentration is non-linearly related
dose to dose
•• Elimination half-life does not change with •• Elimination half-life increases with increase in
increase in dose dose
As is clear from the above example, at drug Km: concentration at which half the maximal
concentration of 200 µg/mL, 50% of the drug is rate of elimination is reached.
excreted in 1 t1/2 but at drug concentration of 400 After single dose administration, concentration
µg/mL it takes double the time for 50% elimination. verses time curve for drugs following zero-order
Therefore, the Cl decreases as the dose increases. kinetics is a steep straight line but is curvilinear if
Hence, the t 1/2 of drugs following zero-order log of concentration is used (Fig. 3.12).
kinetics increases with increase in dose. For such
drugs increase in dose can cause rapid increase in Mixed Order Kinetics
drug concentration to toxic levels especially so for
drugs with narrow therapeutic index. Some drugs like aspirin follow mixed order
For drugs following zero-order kinetics kinetics. The elimination is dose-dependent.
clearance is expressed as follows: At low doses with low drug concentration,
elimination follows first order kinetics but at
Cl = Vm/(km+C) higher drug concentration elimination follows
Vm: maximal rate of elimination zero order kinetics as the metabolizing enzymes
Figure 3.12 Concentration versus time profile for drugs following zero-order kinetics
Figure 3.13 Concentration versus time profile of drugs following mixed kinetics
get saturated. Consequently, after single dose discussed earlier, steady sate can be achieved in
administration, drug concentration versus time a time period equal to 5 t1/2, if repeated doses are
curve is a steep line at higher concentration administered at an interval equal to 1 t1/2. Drugs
but curvilinear at lower concentration. If log of that have very short t1/2 require administration
by continuous infusion. For drugs that have t1/2
concentration is used for plotting the curve, it is
curvilinear at higher plasma concentration and between 30 minutes and 2 hours, it is practically
linear at low plasma concentration (Fig. 3.13). difficult to administer the drug at every t1/2. Such
For drugs following mixed order kinetics, drugs, if have high margin of safety and follow
first order kinetics, can be administered at high
increase in dose can rapidly change the elimination
kinetics from first to zero order causing rapid doses at an interval of 6–8 hours. Increase in
increase in drug concentration and toxicity. dose will increase the duration of action and
sustained therapeutic effect can be obtained
with less frequent administration. Drugs that
MULTIPLE DOSE ADMINISTRATION have t1/2 between 4–12 hours, are administered
AND DOSING SCHEDULE at an interval equal to their t1/2. Drugs that have
a t1/2 of about 24 hours are given in half of the
In therapeutics, multiple dose administration is therapeutic dose every 12 hours. Drugs that have
done to maintain a steady state concentration. As very long t1/2 take very long time to reach steady
state concentration (5 t1/2 is required to achieve Cssav = average steady state concentration,
steady state concentration). In clinical situations F = bioavailability, T = dosing interval.
where immediate response is required such drugs
are administered in loading dose so as to quickly
achieve the target steady state concentration and RATIONAL FIXED DOSE
then this is followed by maintenance doses so as COMBINATIONS
to maintain steady state (Fig. 3.14).
Loading dose = Target drug concentration × Vd Fixed dose combinations are the pharmaceutical
Maintenance dose = Steady state concentration preparations containing two or more drugs.
× Cl Rational fixed dose combinations consist of drugs
with approximately equal half-life. The ratio of the
Loading dose is often large and is associated dose of each component depends upon the desired
with the risk of toxic effects. To reduce the risk of plasma concentration for optimal efficacy, which
toxicity, loading dose can be divided into multiple in turn depends upon the drug’s V . For example,
small doses administered over a period of time. cotrimoxazole is a synergistic combination
d
of
Intermittent administration of multiple doses
sulfamethoxazole and trimethoprim in a ratio of
results in fluctuating plasma drug concentration,
1:5. The half life of two drugs is similar and 1:5
which varies between a peak and a trough
ratio gives a required optimal serum concentration
concentration. At steady state this variation
of 1:20 (trimethoprim: sulfamethoxazole) due to
is repeated identically during each interdose
larger Vd of trimethoprim.
interval. Reduction in dose and dosing interval
Fixed dose combinations provide a convenient
reduces the amplitude of fluctuations. Mean
dosing schedule and may allow reduction in the
steady state concentration does not depend on Vd.
dose of individual component drugs, thereby,
It is not determined by loading dose but is directly
reducing the risk of adverse effects. Although the
proportional to maintenance dose and indirectly
fixed dose combinations provide better patient
proportional to clearance. Mathematically, steady
compliance but if required, doses of individual
state concentration can be calculated as follows:
components cannot be altered. Moreover, the
Cssav =
F × Dose component primarily responsible for benefits or
Clearance × T adverse effects cannot be determined. Therefore,
Figure 3.14 Steady-state achieved after loading and maintenance dose

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drugs. Sur Ophthalmol. 1993;37(6):435–56. metabolism of ocularly applied levobunolol in
28. Hornof M, Toropainen E, Urtti A. Cell culture the pigmented rabbit. J Pharmacol Exp Ther.
models of the ocular barriers. Eur J Pharm 1988;246:871–8.
Biopharm. 2005;60:207–25. 36. Jones RF, Maurice DM. New methods of
29. Zhang T, Xiang CD, Gale D, Carreiro S, Wu measuring the rate of aqueous flow in man with
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implications for ocular drug disposition. Drug distribution volume measurement in rabbits. J
Met Dispos. 2008;36(7):1300–7. Pharm Sci. 1977;66(2):219–24.
ChapteR 4
Pharmacodynamics
OVERVIEW of drug with receptors is usually specific and

reversible, but it can be irreversible if the drug
Pharmacodynamics is the study of biochemical forms a covalent bond with the receptor such as
and physiological changes that the body undergoes the organophosphate compounds.
after drug administration. It includes the study Drugs acting through receptor mediated
of the site and mechanisms of drug action and mechanisms are classified in four groups
describes the relationship of drug’s plasma depending upon their two properties:
concentration with its response. 1. Affinity, which refers to the ability of the drug
The site of action of drug can be on the cell to bind the receptor.
surface such as via receptors or intracellular such 2. Intrinsic activity, which refers to the ability
as interference with cellular metabolic pathways of the drug to trigger the pharmacological
or gene transcription. The mechanisms by which response after binding.
drugs bring about biochemical and physiological
Agonists are the drugs that have both the affinity
changes can be receptor mediated or non-receptor
and intrinsic activity (IA = 1), i.e. they bind with
mediated. Both the receptor and non-receptor
the receptor and initiate the pharmacological
mediated mechanisms can occur on the cell
response. In other words they fit into the lock and
surface or intracellularly.
open it (Fig. 4.1). Pilocarpine is an agonist and its
interaction with cholinergic muscarinic receptors
RECEPTOR-MEDIATED MECHANISMS in the circular muscle of iris and ciliary body
produces pupillary constriction and cyclospasm.
OF DRUG ACTION
Antagonists are the drugs that have the affinity
Most of the drugs produce their actions by for the receptor but no intrinsic activity (IA = 0).
interaction with macromolecular proteins known They bind with the receptor, do not activate the
as receptors that can be present either on the cell pharmacological response and at the same time do
surface or inside the cell. The receptors interact not allow interaction of receptor with the agonist.
with the functional groups on drug molecules or Antagonists, that have structural similarity with
endogenous substances. The three dimensional agonist, compete with agonist for the same
structure of receptors and drugs fits into each receptor site. Receptor-antagonist binding is
other just like a key in the lock resulting in the usually by means of hydrogen bonds, which
formation of a drug-receptor complex. Formation are weak linkages and allow easy separation
of drug-receptor complex triggers reactions of antagonist from receptor. Such competitive
leading to biological response. This interaction antagonism is, therefore, reversible. Atropine
Pharmacodynamics 51
Figure 4.1 Drug-receptor interactions
is a competitive antagonist and its binding with at G-protein coupled rhodopsin in the outer
muscarinic receptors prevents the binding of segments of rods.2
acetylcholine (agonist) at muscarinic receptors
in the circular muscle of iris and ciliary body Two State Model of Receptor-
producing pupillary dilation and cycloplegia.
mediated Drug Action
However, if the receptor antagonist interaction
is by means of strong covalent bonds, the The difference in the response (agonist or
antagonism is irreversible. Antagonists can antagonist) to two drugs binding the same receptor
also interact with receptor at sites other than with same affinity can be explained on the basis
the agonist-binding site, i.e. non-competitive of “the concept of dual nature of the receptors”.3
antagonism. Such an interaction induces change According to this model receptors exist in two
in the configuration of agonist binding site of the conformations: active and inactive; and the two
receptor and, therefore, interferes with agonist- states exist in equilibrium. The drugs alter this
receptor binding (Fig. 4.1). state of equilibrium depending upon their relative
Partial agonists are the drugs that have both the affinity for the two types of receptor conformations.
affinity and intrinsic activity but their intrinsic Agonists have high affinity for activated
activity is less than the agonist (IA = zero to receptor conformation, therefore, shifting the
1). Therefore, the pharmacological response equilibrium in favor of activated form of the
produced is less than that of an agonist. (Fig. 4.1). receptors whereas antagonists have equal affinity
Carteolol, a beta adrenoreceptor blocker, used in for activated and inactivated receptors, thereby
the treatment of glaucoma is a partial agonist. It maintain the equilibrium without a shift in any
occupies the beta receptors, prevents stimulation direction. Partial agonists have higher affinity
of these receptors by beta agonists and has some for activated form of the receptors and shift the
stimulant activity of its own.1 equilibrium towards activated form but to a lesser
Inverse agonists are the drugs that have affinity degree as compared to agonist. Inverse agonists
for the receptor but the response produced is have higher affinity for inactivated form and shift
opposite to that of an agonist [IA = zero to (–1)] the equilibrium towards the inactivated form of
(Fig. 4.1). The 11-cis retinal is an inverse agonist the receptor (Fig. 4.2).
Figure 4.2 Drug actions based on dual nature of Figure 4.3 Ionotropic receptor
receptors
Types of Receptors (GPCR). GPCR consist of seven transmembrane

helical domains with their N-terminal placed
Receptors differ in their molecular structure extracellularly and C-terminal intracellularly.
and the post-receptor transduction mechanisms The intracellular terminal of GPCR is coupled
leading to differences in cellular responses. with trimeric G-proteins.5 The three subunits
Accordingly, they are grouped into four receptor of G-proteins include α, β and γ. When the
families: receptor is in inactivated state the subunits are
1. Ionotropic receptors (Type I receptors): This coupled with GDP. Interaction of agonist with
family of receptors incorporates an ion channel receptor causes conformational change in the
within it. Binding with the agonist, opens the receptor triggering the exchange of GDP with
ion channel causing membrane depolarization GTP. Following the inclusion of GTP into the
or hyperpolarization (Fig. 4.3). The receptors agonist-receptor-G protein complex, GTP-α and
for excitatory neurotransmitter glutamate in β-γ subunits dissociate from the complex. GTP-α
retina are ionotropic receptors. Their activation subunit interacts with target molecule (effector
by glutamate increases the flow of calcium into system) and in the process GTP gets hydrolyzed
the cells initiating the excitatory functions. For to GDP. GDP-α complex so formed dissociates
inhibitory neurotransmitter GABA, two subtypes from the target molecule, reunites with β-γ
GABAA and GABAc, are ionotropic receptors. subunit and returns the receptor to inactivated
GABAC receptors are highly expressed in retina, state (Fig. 4.4).
mainly localized at the axon terminals of bipolar G-proteins act via one of the three effector
cells. 4 Both the receptor types incorporate a systems, which form the second messenger
chloride channel. Opening of these channels systems for post receptor signal transduction:
in response to interaction with GABA causes 1. Adenylyl cyclase: Cyclic AMP system
inward flow of chloride ions causing membrane 2. Phospholipase C: Inositol phosphate system
hyperpolarization. Some drugs allosterically 3. Ion channel regulation
enhance the effect of endogenous substance Distinctive properties of α subunit determine
on channel opening such as benzodiazepines its binding specificity with the type of effector
facilitate action of GABA on GABAA receptors. system and accordingly, G-proteins can be of
Ascorbic acid has been shown to potentiate the three types: Gs, Gi and Gq, Gs and Gi stimulate and
effects of GABA by allosteric modulation of the inhibit adenylyl cyclase respectively. Gq affects
ionotropic GABA receptors. the phospholipase C activity.
2. Metabotropic receptors (Type II receptors): Adenylyl cyclase-cAMP system: The enzyme
These receptors are present on the cell surface and adenylyl cyclase may be the target following
are also known as G-protein coupled receptors interaction of agonist with the receptors and
Pharmacodynamics 53
Figure 4.4 G-protein linked metabotropic receptor activation
Figure 4.5 Second messenger system activation by G-proteins
activation of G-protein. As a result the enzymatic kinase A. Stimulated protein kinase A causes
activity may get stimulated or inhibited leading sustained stimulation of Na+ K+ Cl- cotransport
to increase or decrease in the cellular levels of leading to increased aqueous humor formation.6,7
cAMP. Increased cAMP causes activation of Stimulation of prejunctional α2 adrenergic
protein kinase A, which in turn phosphorylates receptors in iris-ciliary body is negatively coupled
various proteins, thereby altering the cellular with adenylyl cyclase and, therefore, reduces
function (Fig. 4.5). For example: The non- cellular cAMP level.7-9
pigmented ciliary epithelium has rich distribution Phospholipase C-Inositol phosphate system:
of β2 adrenergic receptors, which are GPCR. Activation of Gq proteins in response to interaction
Stimulation of these receptors causes activation of agonist with receptor causes activation of
of adenylyl cyclase leading to increased cellular membrane-bound phospholipase C (PLC).
cyclic AMP levels, which stimulates protein Activated PLC causes hydrolysis of inositol 4,
Figure 4.6 Transmembrane signaling by tyrosine kinase linked receptors
5-diphosphate (PIP2), a phospholipid component causing membrane hyperpolarization and reduced

of plasma membrane. As a result of hydrolysis, neurotransmitter release.11
PIP2 splits into diacylglycerol (DAG) and inositol
3. Enzyme-linked receptors (Type III receptors):
1, 4, 5-triphosphate (IP3). IP3 diffuses out into
These transmembrane receptors have an
the cytoplasm and causes release of Ca2+ from
extracellular domain for binding with the ligand
intracellular storage sites. The released Ca 2+
(agonist) and an intracellular domain linked to an
binds to Ca2+ binding protein calmodulin, which
then regulates activity of various enzymes and enzyme such as tyrosine kinase. Agonist binding
produces responses like contraction and secretion. with the receptor causes conformational changes in
DAG activates Ca2+ sensitive protein kinase C, receptor leading to receptor autophosphorylation,
which in turn causes phosphorylation of proteins dimerization and activation of tyrosine kinase.
and brings about the cellular responses. Action Activated tyrosine kinase activates intracellular
of IP3 is terminated by its dephosphorylation signaling proteins leading to altered cellular
to phosphotidyl inositol monophosphate (PIP), functions (Fig. 4.6). Examples of this type of
a precursor of PIP 2 (Fig. 4.5). DAG is either receptors include insulin receptors, growth
converted back to phospholipids or gets acetylated hormone receptors. Nitric oxide receptors have
to arachidonic acid. Ca2+ returns back to storage guanylyl cyclase at their intracellular domain
sites by active transport. Examples of this type instead of tyrosine kinase. Receptor activation
of receptors include muscarinic receptors, α1 by ligand binding causes synthesis of a second
adrenergic receptors.10 messenger, cyclic GMP, that brings about cellular
responses.
Ion channel regulation: Some of the GPCR
regulate opening or closure of ion channels in 4. Cytoplasmic receptors (Type IV receptors):
response to interaction with agonists without The cytoplasmic receptors are precisely nuclear
intervening second messengers. For example: receptors. Interaction with ligand at their ligand
rhodopsin located in the disc membrane of binding domain unmasks their DNA-binding
the outer segment of rods is a GPCR. Upon domain. The unmasked DNA-binding domain now
activation by light, the covalently attached binds with the DNA of specific genes and activates
chromophore 11-cis retinal isomerizes to all- RNA polymerase. Activated RNA polymerase
trans retinal. Isomerization causes G-protein leads to synthesis of a specific m-RNA, which
activation and dissociation of α subunit and directs synthesis of specific proteins and produces
activation of phosphodiesterase that hydrolyzes cellular responses (Fig. 4.7). Examples of this type
cyclic GMP. Reduced cellular cyclic GMP causes of receptors include steroid hormone receptors,
closure of cGMP-sensitive sodium channels thyroid hormone receptors.
Pharmacodynamics 55
Figure 4.7 Regulation of DNA transcription by steroids through

intracellular receptors
Modified Receptor Actions number of receptors respond excessively to

endogenous catecholamines leading to rebound
Desensitization refers to reversible reduction hypertension. Therefore, in such cases the drugs
of receptor mediated response upon continued should be withdrawn by gradually tapering the
exposure to agonist. Continued exposure to dose with close clinical monitoring.
agonist causes conformational changes in receptor
Spare receptors refer to receptor reserve of
leading to tight binding with agonist without
the tissue. To achieve the peak effect it is not
producing the effect such as channel opening
necessary that all the receptors are occupied by the
at nicotinic neuromuscular junction receptors
drug molecules. Higher is the proportion of spare
or inability to activate adenylyl cyclase at
receptors for a drug in a tissue, higher is the tissue
adrenoreceptors.
sensitivity to that drug. For example: myocardium
Supersensitivity, upregulation and down- requires only 10% of its receptors to be occupied
regulation of receptors refer to increased or by catecholamines for peak effect and accordingly
decreased receptor sensitivity/expression on even if 80–90% of the catecholamine receptors
prolonged exposure to antagonist or agonist, are blocked, peak effect to catecholamines can
respectively. Continued exposure to antagonist still be elicited. This indicates high sensitivity of
causes increased number of receptors due to myocardium to catecholamines.
externalization of more receptors (upregulation).
Moreover, the sensitivity of receptors to available
agonists increases (supersensitivity). On the NON-RECEPTOR MEDIATED
other hand, continued exposure to agonist causes MECHANISMS OF DRUG ACTION
receptor internalization leading to decreased
Drugs may act by mechanisms other than receptor
number of receptors and decreased sensitivity.
mediated. Some of the non-receptor mediated
Prolonged treatment of bronchial asthma with
mechanisms of drug action are as follows:
β2 agonist causes reduction in response over
a period of time. This is because of receptor Chemical Reactions: Drugs may react chemically
downregulation. Receptor upregulation may be with endogenous substances to bring about
responsible for excessive rebound agonist action changes in physiological functions. For example:
after sudden withdrawal of a drug following long- antacids react with hydrochloric acid in stomach
term exposure leading to serious consequences. to neutralize it and, thereby reduce hyperacidity,
For example prolonged treatment of hypertension deferoxamine chelates with iron and facilitates
with non-selective β-blockers causes receptor excretion of excessive iron stored following
upregulation as well as supersensitivity. If the repeated blood transfusions, cholestyramine lowers
β-blockers are suddenly withdrawn, increased cholesterol level by exchanging with chloride ions
in bile salts and increasing its excretion. Inducing Antibody Formation: Vaccines, either
Physical Actions: Drugs may cause changes in by inducing antibody formation or by providing
physiological functions by virtue of their physical passive immunity, are effective in the prevention
properties. Mannitol reduces intraocular pressure and treatment of diseases. For example: smallpox
by drawing water out of intraocular tissue due vaccine, diphtheria antitoxin.
to its hyperosmolarity. Saline purgatives exert
high osmotic pressure in the lumen of gut. MEASUREMENT OF DRUG EFFECTS
Demulcents like pectin provide a protective
covering to inflamed mucosa and have soothing 1. Graded dose-response curve : The responses
effect. Astringents like tannic acid denature and following drug administration require
precipitate mucosal proteins and, thereby protect quantitative assessment in order to evaluate
mucosa by firming it up. Adsorbants like kaolin its safety and efficacy. Quantitative assessment
adsorb bacterial toxins and are useful as anti- of the magnitude of response as a function
diarrheal agents. of dose can be done using graded dose-
Targeting Enzymes: Some drugs act by response curve. It provides assessment of the
inhibiting the enzyme action, thereby altering relationship of the different doses (graded
the endogenous chemical reactions. For example: dose) with the corresponding responses in a
allopurinol, inhibits the enzyme xanthine oxidase, single individual/animal/isolated tissue. The
thereby reduces the synthesis of uric acid and is horizontal axis represents the dose while the
effective in the treatment of gout. Physostigmine vertical axis represents the response. The dose
inhibits acetylcholinesterase at neuromuscular on the horizontal axis is commonly plotted
junctions, thereby increases the availability of in ‘log’ scale. This helps in accommodating
acetylcholine and causes pupillary constriction wider dose range on a small graph paper and
and reduced intraocular pressure. Sulfonamides converts the hyperbolic curve (if arithmetic
act as antibacterial agents by competing with dose scale is used) into a sigmoid shape (if
p-amino benzoic acid and replacing it in the log dose scale is used). (Fig. 4.8)
synthesis of folic acid in bacteria; resultant Graded dose-response curve is useful for the
compounds are nonfunctional. assessment of the:
Protoplasmic Poisons: Antiseptics like 1. ED 50 from its linear segment. ED 50 is the
formaldehyde act as non-specific protoplasmic dose that produces 50% of the maximum
poison and kill the microorganism. response.
Figure 4.8 Graded dose-response curve

Pharmacodynamics 57
2. Potency of the drug. Potency refers to the people showing a particular response. Here the
amount of drug needed to produce a particular response is prefixed such as 20% fall in blood
response. The relative potency of drugs can be pressure from baseline. The response can also be
assessed by comparing the placement of the prefixed as ‘all or none’ response such as death
curve in relation to each other on horizontal or no death. It is a frequency distribution curve,
axis (Fig. 4.9). which shows frequency distribution of the doses of
3. Efficacy of the drug. Efficacy refers to the drugs required to produce a specified effect, i.e. the
maximal response that the drug can produce. percentage (%) of people that require a particular
Relative efficacy of drugs can be assessed dose to exhibit specified effect. A cumulative
by comparing the height of the curves (Fig. frequency distribution curve derived from quantal
4.9). dose response curve is a sigmoid curve (Fig. 4.10).
Quantal dose-response curve: This curve Quantal dose-response curve
provides an assessment of the relationship of 1. Does not tell about the magnitude of the
the different doses with the percentage (%) of response as the response is “prefixed”.
Figure 4.9 Potency and efficacy
Figure 4.10 Quantal dose response curve

2. Is a frequency distribution curve and indicates
the number of subjects (frequency) showing a
“prefixed” response to a certain dose.
3. Provides information about the individual
variations within a group.
4. Provides information about the optimal
therapeutic dose range to which most of
the patients show the desired response. The
corresponding range of plasma concentrations
of the drug is called its “therapeutic window”.
5. Can be converted to a cumulative frequency
curve by plotting the doses on the horizontal
axis and the cumulative percentage of
individuals showing prefixed response on Figure 4.11 Therapeutic index
vertical axis. Cumulative percentage for a
certain dose is calculated by summation of FACTORS AFFECTING DRUG
the percentage of individuals responding to it RESPONSES
and to all doses below this dose. It is a sigmoid
curve that allows calculation of ED50 and LD50. Drug Related Factors
6. Can be used to calculate ED50 which indicates
the dose that is effective in 50% of the The dose and the dosage form: The dose, i.e.
subjects. LD50 is the dose, which is lethal to the absolute amount of drug administered and
50% of the experimental subjects. the dosage form, i.e. the method or the form in
which the drug is administered, both modify the
drug responses. Increasing the amount of drug
MEASUREMENT OF DRUG SAFETY administration increases the risk of toxicity, more
so in case of drugs with narrow therapeutic margin.
The aim of drug therapy is to produce desired The dosage form needs to be selected according to
beneficial therapeutic effects without producing the pathological state to obtain optimum response.
hazardous effects. “Therapeutic index” is For example, sustained release preparations
an indicator of relative safety of drug and is provide a longer duration of action.
calculated as below (Fig. 4.11): The route of administration: The drug
TI = LD50/ED50 responses vary according to the chosen route of
administration. For example, inhaled salbutamol
Larger the LD50 as compared to ED50, safer
more quickly relieves the bronchospasm as
is the drug. “Certain safety factor” is a better
compared to orally administered salbutamol.
indicator of drug’s safety as it compares the dose,
which is effective in 99% of individuals with the The dosing interval: The dosing interval
dose that is lethal in 1% of the individuals. may greatly affect the therapeutic outcome.
For example: Once daily administration of
Certain safety factor (CSF) = LD1 /ED99
aminoglycosides is less likely to cause ototoxicity
Relative safety of a drug can also be expressed as compared to more frequent administration
in terms of “standard safety margin”, which is during the day.
calculated as below:
The duration of drug administration: The total
Standard safety margin = [(LD1 – ED99)/ duration of therapy influences the therapeutic
ED99]×100 outcome. For example, long-term glucocorticoid
Pharmacodynamics 59
therapy is likely to be associated with more Pathological state: The drug responses are
adverse effects as compared to short-term therapy. modified by individual’s metabolic, biochemical
The time of drug administration: The time and pathological status usually due to changes
of administration during the day can affect in drug disposition. For example, patients
the response to drugs. For example: Sedatives with impaired renal functions are more likely
produce sedation with smaller doses if given at to experience ototoxic adverse effects of
night as compared to when given during the day. aminoglycosides; patients with malabsorption
show decreased absorption of amoxicillin but
higher absorption of cotrimoxazole; hyperthyroid
Patient Related Factors individuals are relatively less sensitive to morphine
Age: The drug responses vary in relation to age but highly sensitive to sympathomimetics.
and the doses required for children are different Emotional and psychological state: Some
from the adult doses. In children, body surface individuals show therapeutic response to placebo
to mass ratio is considerably higher than that (pharmacologically inactive constituents)
of adults and accordingly doses for children are whereas others may collapse while entering
calculated on the basis of body surface area. As the operation theater and may show altered
it may be cumbersome to calculate body surface response to drugs due to altered emotional and
area for all patients, nomograms can be used that psychological state.
provide information about body surface area
based on height and weight.
MODIFIED DRUG RESPONSES
Body weight: Average adult dose is calculated,
based on the efficacy in 50% of adults, 18–65 Drug tolerance: Tolerance refers to the inability
years of age, and weighing about 70 kg. Therefore, to produce the response of same magnitude
abnormally lean or obese individuals require dose following repeated administration of a drug and an
adjustment. This is because the proportion of increase in dose is, therefore, required to produce
body water is higher in lean as compared to obese the same effect. Development of tolerance causes
individuals. the dose-response curve to shift parallel to the
Sex: Drug responses may be different in males and right. Intermittent dosing of some drugs like
females. For example: Barbiturates can produce cocaine causes increased responsiveness over a
period of time and this phenomenon is known
excitation in females before sedation. Beta-blockers
as sensitization. Sensitization causes the drug-
reduce libido only in males. Pregnancy and
response curve to shift to left.
lactation may also require alteration in doses due to
Development of tolerance is a relatively
alterations in drug disposition. During pregnancy,
common phenomenon, often observed with
plasma albumin levels reduce but plasma α1-acid
drugs acting on the central nervous system. The
glycoprotein levels increase. Therefore, the fraction
tolerance may not develop to all pharmacological
of unbound form of the acidic drug increases but actions of a drug. For example, repeated use of
that of basic drug decreases. morphine results into development of tolerance
Genetic variations: Some individuals may have to its most pharmacological effects but not for
a drug response different from the normally miosis and constipation. Tolerance to a drug can
observed response due to genetic variations. be natural, acquired or cross tolerance.
For example, deficiency of the enzyme glucose- Natural tolerance is genetically determined
6-phosphate dehydrogenase predisposes to and is observed after the administration of
hemolytic anemia, deficient activity of pseudo first dose. For example, rabbits are tolerant to
cholinesterase predisposes to apnoea in response atropine, Blacks are tolerant to mydriatic action
to very small doses of succinylcholine. of sympathomimetics.
Acquired tolerance develops following repeated can not be obtained even after increasing the
administration of a drug in an individual who dose. Drugs like ephedrine and amphetamine act
was initially responsive to the drug. This type of by releasing catecholamines from storage sites.
tolerance can develop either due to alterations However, repeated administration of these drugs
in drug disposition (known as pharmacokinetic causes depletion of catecholamines from storage
tolerance) or due to adaptive changes in the sites without a chance of replenishment. Therefore,
target tissue (known as pharmacodynamic following repeated administration, these drugs fail
tolerance). Tolerance to some drugs results from to produce the same pharmacological response.
both the pharmacokinetic and pharmacodynamic Prolonged exposure to nitrates also causes
alterations. development of tolerance as is the case in workers
Pharmacokinetic tolerance results when the exposed to nitroglycerine. These workers develop
drug reduces its own absorption, induces its headache at the beginning of the week due to
own metabolism or increases its own excretion, exposure to nitroglycerine but as the exposure
thereby requiring larger doses to produce continues during the week, headache disappears by
similar pharmacological effects after repeated Friday due to tachyphylaxis. However, when the
administration. For example, alcohol reduces its workers return to work on Monday after staying
own absorption after repeated consumption due away from nitroglycerine during the weekend, the
to thickened gastric mucosa, barbiturates induce headache reappears. Tachyphylaxis is rarely seen
the metabolizing enzymes and increase their in clinical practice as the repetitive administration
own metabolism, amphetamine promotes its own over a short period of time is not customary.
excretion after repeated administration as a result Cross tolerance can develop among the drugs
of acidification of urine due to reduced food intake belonging to the same category. For example,
and development of ketosis. The log plasma people tolerant to morphine are also tolerant to
concentration-response curve after development heroin.
of pharmacokinetic tolerance remains unchanged Drug interactions: Concurrent administration
as the increased dose compensates of the losses of two or more drugs may lead to modified drug
in the process of drug disposition, while the response. The modified drug response may appear
relationship between plasma drug concentration as a summative effect, additive effect, synergistic
and response remains unchanged. effect or antagonistic effect.
Pharmacodynamic tolerance develops due Summation of the drug responses is observed
to altered reactivity of the target tissue. After when two drugs administered concurrently
repeated administration, the response of the target produce same effect by acting through two
tissue is less despite the same plasma level. Hence, different mechanisms. Aspirin and codeine both
to obtain the same degree of response higher produce analgesia but act through different
plasma concentration is required as compared to mechanisms. Therefore, the degree of analgesia
initial plasma concentration. This is reflected by produced by concurrent administration of
the shift of log plasma concentration-response aspirin and codeine is equal to the sum of
curve to right. Some of the drugs that cause analgesic effects produced by each of them when
pharmacodynamic tolerance include morphine, administered individually.
nicotine, caffeine. Additive effect is also the sum total of the
Acute tolerance or tachyphylaxis refers to individual responses when two drugs are
development of the acute tolerance following administered concurrently. However, the two
rapid, repetitive administration of a drug at short component drugs produce the same effect by
intervals. Tachyphylaxis appears quickly after acting through same mechanism. For example,
repetitive doses and the original drug response aspirin and paracetamol.
Pharmacodynamics 61
Synergistic effect is observed when the response Pharmacokinetic antagonism is observed when
following concurrent administration of two drugs is one drug alters the absorption, metabolism
more than the sum total of their individual effects. or excretion of other drug, if coadministered.
The outcome of the synergistic effect may be in Phenytoin reduces the efficacy of warfarin by
the form of potentiation of activity, prolongation inducing cytochrome enzymes and enhancing its
of the duration of action or both. For example: metabolism.
combination of sulfamethoxazole and trimethoprim
Pharmacodynamic antagonism between two
is bactericidal although each of these drugs is
drugs is receptor mediated. As defined earlier,
bacteriostatic when administered individually.
antagonists have affinity for the receptor but no
This synergism is attributed to sequential action
intrinsic activity. They occupy the receptor and
of the two drugs on two different steps in the
same metabolic pathway for bacterial folic acid do not allow agonist to interact with it, thereby
synthesis. Hypertensive crisis observed after co- blocking the action of agonist. The receptor
administration of tyramine and monoamine oxidase mediated antagonism may be of the following
inhibitors (MAOI) is also an example of synergistic types:
effect. MAOIs inhibit metabolism of tyramine, 1. Reversible (competitive or equilibrium type)
which is then available in large quantities to release antagonism: The antagonist competes with
catecholamines causing hypertensive crisis. the agonist for the same receptor type and
Antagonism is observed when the response binds with it reversibly. However, if the
following concurrent administration of two concentration of agonist is increased the
drugs is less than the sum total of their individual antagonism may be overcome and maximal
effects. Antagonistic effects may be due to effect can be achieved, i.e. the antagonism
chemical antagonism, physiological antagonism, is surmountable. This is because the binding
pharmacokinetic antagonism or pharmacodynamic of antagonist is reversible and it dissociates
antagonism. easily from the receptors, which gradually
Chemical antagonism appears due to chemical become occupied by increasing concentration
interaction between two drugs. For example, of agonist along with the spare receptors.
tetracyclines are chelated by divalent cations This establishes a new equilibrium and
in antacids, thereby reducing the absorption hence is also known as equilibrium type of
of tetracycline. Negatively charged heparin is antagonism. As a higher quantity of agonist
antagonized by positively charged protamine, is required to produce the same effect in
which is used to terminate the action of heparin. the presence of antagonist, ED50 increases.
Antacids act simply by neutralizing the acid in Presence of reversible antagonist causes the
stomach. Deferoxamine facilitates excretion of agonist dose-response curve to shift in parallel
iron by chelating with it.
to right (Fig. 4.12). For example, atropine acts
Physiological antagonism refers to counter as a competitive antagonist of acetylcholine
balancing the opposite actions of two drugs on at muscarinic receptors.
the same physiological system. This antagonism 2. Irreversible (non-equilibrium type) anta
results from opposite responses and the ability of gonism: Irreversible antagonism is observed
each drug to produce its own effect is uninhibited. when the antagonist binds with the same
For example: Effect of CNS depressants is receptor as the agonist but this binding
antagonized by stimulants. Vasoconstrictors with receptor is irreversible due to covalent
antagonize the effects of vasodilators. bonds. The strong covalent bonds make
Figure 4.12 Shifting of agonist dose-response curve in Figure 4.13 Shifting of agonist dose-response curve in
presence of reversible antagonist presence of irreversible antagonist
the antagonist dissociate very slowly or verapamil blocks Ca++ channels and, therefore,
not at all from the receptors. Therefore, blocks norepinphrine-induced myocardial
by increasing the concentration of agonist, contraction without interacting with the β
antagonist occupancy does not change to receptors.
establish a new equilibrium (non-equilibrium 4. Negative antagonism: These antagonists
type) and hence the antagonism can not be occupy the receptors and produce effects
surmounted (insurmountable). As the higher opposite to that of agonists. For example,
concentration of agonist fails to overcome negative antagonism of β-carbolins at
the antagonism, maximal effect can not be benzodiazepine receptors.
achieved and the agonist dose-response curve
shifts down and to the right in the presence of
irreversible antagonist (Fig. 4.13). Example; OUTCOMES OF MULTIPLE DRUG
irreversible inhibition of acetylcholinesterase THERAPY
by organophosphate compounds. Some
antagonists like phenoxybenzamine may Multiple drugs are often administered in clinical
not exhibit typical feature of irreversible practice. This can be done either as concurrent
antagonism initially due to smaller receptor administration of more than one drug or as a
occupancy by the antagonist and availability fixed dose combination of more than one drug in
of spare receptors to agonist. However, a single dosage form. The outcome of the multiple
eventually with increasing concentration of drug therapy may be in the form of:
antagonist, typical features of irreversibility i. An adverse effect due to reduced efficacy or
are observed. increased toxicity of one of the drug due to
3. Non-competitive antagonism: This type of the presence of another. This type of effect
antagonism is observed when the antagonist is further discussed in the next section.
binds at a site other than the receptor for ii. A beneficial effect due to enhanced efficacy
agonist. This binding alters the receptor or reduced toxicity of one of the drug due
configuration so that it can no longer bind with to the presence of another. For example,
the agonist. Alternatively, the antagonist may combination of levodopa with carbidopa
block a particular step in the chain of events increase the availability of dopamine in
leading to agonist response. For example, brain.
Pharmacodynamics 63
iii. Interference with the diagnostic laboratory Expected Adverse Drug Reactions
tests. For example, salicylates give a positive (Type A–ADRs)
test for urine sugar, estrogens cause a false
positive rise in serum thyroxin values. These are predictable adverse drug reactions that
are related to pharmacological actions of the drug
Adverse Effects due to Drug-Drug and are dose-related.
Interactions Side-effects are undesirable but unavoidable
adverse effects observed with the therapeutic
The drug-drug interactions manifesting in the doses of drugs and are mild and dose-related.
form of reduced efficacy or enhanced toxicity For example, promethazine when used for anti-
may be observed in vitro or in vivo. allergic action also causes sedation, dicyclomine
In vitro drug-drug interactions occur due to relieves abdominal pain but also causes dry
mixing of incompatible drugs prior to admin mouth.
istration. For example, mixing penicillin and Secondary effects are due to major pharmacological
aminoglycosides in the same syringe. action of drug and are predictable. For example,
In vivo drug-drug interactions occur due to baclomethasone inhalation causes oral candidiasis
pharmacokinetic or pharmacodynamic interaction. due to reduced local immunity, broad spectrum
Pharmacokinetic drug-drug interaction leading antibiotics predispose to superinfection by
to adverse effects can be due to: suppressing the intestinal bacterial flora.
i. Altered absorption: Reduced tetracycline Toxicity can occur due to exaggerated pharma-
action due to chelation with antacids. cological action such as due to overdoses or
ii. Altered distribution: Excessive warfarin prolonged use and is predictable. For example,
action due to displacement form protein bleeding due to high doses of heparin, nephro-
binding sites by sulfonamides. toxicity to aminoglycosides.
iii. Altered metabolism: Reduced efficacy of oral
contraceptives due to metabolizing enzyme Unexpected Adverse Drug
stimulation by rifampicin.
Reactions (Type B – ADRs)
iv. Altered excretion: Enhanced excretion
of barbiturates in alkaline urine and These are unpredictable adverse drug reactions
amphetamine in acidic urine. that are not related to pharmacological actions of
the drug and are not dose-related.
Pharmacodynamic drug-drug interactions
leading to adverse effects can be due to: Allergy or Immunologically mediated adverse
drug reactions occur due to prior exposure to drug
i. Additive or summative action: Digitalis +
propranolol cause severe bradycardia. that initiates an immunological response. It can
ii. Altered ionic balance: Diuretics increase be a type I immune reaction such as anaphylaxis;
digitalis toxicity by causing hypokalemia. type II immune reaction such as drug-induced
iii. Altered neuronal uptake of neurotransmitters: hemolysis; type III immune reaction such as drug-
Imipramine blocks action of clonidine by induced glomerulonephritis or type IV immune
inhibiting neuronal norepinephrine uptake. reaction such as drug-induced contact dermatitis.
Drugs within the same group often exhibit cross
allergy.
ADVERSE DRUG REACTIONS
Genetically determined adverse drug reactions are
Undesirable, untoward or adverse drug reactions observed due to single gene mutation leading to
can be classified into expected adverse drug qualitatively different drug response. For example,
reaction or unexpected adverse drug reaction. presence of atypical pseudocholinesterase causes
excessive response to succinylcholine; isoniazid 3. Vauquelin G, Van Liefde I. G protein-coupled
causes neurotoxicity in slow acetylators due to receptors: a count of 1001 conformations. Fund
accumulation; deficiency of glucose-6-phosphate Clin Pharmacol. 2005;19(1):45–56.
dehydrogenase predisposes to hemolysis by 4. Cecilia I, Calero CI, Vickers E, Cid GM, Aguayo
drugs with oxidizing properties like primaquine LG, von Gersdorff H, et al. Allosteric modulation
of retinal GABA receptors by ascorbic acid. J
and sulfonamides; individuals deficient in
Neurosci. 2011;31(26):9672–82.
uroporphyrinogen synthetase are at risk of
5. Zong H, Neubig RR. Regulator of G protein
developing attacks of intermittent porphyria signaling proteins: novel multifunctional drug
when administered wit h drugs like barbiturates targets. J Pharmacol Exp Ther. 2001;297(3):
or phenytoin. 837–45.
Idiosyncratic reactions occur in minority of 6. Caprioli J, Sears M. The adenylate cyclase
individuals and can be fatal at times. Their receptor complex and aqueous humor formation.
cause is undetermined. For example, malignant Yale J Biol Med. 1984;57(3):283–300.
hyperpyrexia in response to succinylcholine, 7. Crook RB, Riese K. Beta-adrenergic stimulation
aplastic anemia in response to single dose of of Na+, K+, Cl- cotransport in fetal nonpigmented
chloramphenicol. ciliary epithelial cells. Invest Ophthalmol Vis Sci.
1996;37(6):1047–57.
Carcinogenicity, i.e. ability of the drug to cause 8. Jumblatt JE. Prejunctional alpha 2-adrenoceptors
malignancy, is a known adverse effect with some and adenylyl cyclase regulation in the rabbit
drugs like estrogen, radio-isotopes. iris-ciliary body. J Ocul Pharmacol. 1994;10(4):
Teratogenicity refers to drug-induced birth 617–21.
defects. Drugs like thalidomide, penicillamine, 9. Bausher LP, Gregory DS, Sears ML. Alpha
warfarin, phenytoin, valproate and many others 2-adrenergic and VIP receptors in rabbit ciliary
are associated with teratogenic adverse effects. processes interact. Curr Eye Res. 1989;8(1):
47–54.
10. Caulfield MP, Birdsall NJM. International
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2. Milligan G. Constitutive activity and inverse K, Walter P. Signaling through G-protein-linked
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current perspective. Mol Pharmacol. 2003;64(6): Cell, 4th edn. Alberts B et al. (eds.) New York:
1271–6. Garland Science; 2002.pp 852–62.
ChapteR 5
Ophthalmic Formulations and Ocular
Drug Delivery
Overview Table 5.1 Function of excipients
Eye has unique anatomical and physiological 1. To act as solvent for active ingredient
characteristics. Administration of ophthalmic 2. To adjust required concentration
medications on the ocular surface or inside the 3. To adjust tonicity
eye requires specially formulated preparations 4. To adjust pH
that are compatible with ocular tissue. Ophthalmic 5. To prevent microbial contamination
formulations are developed to optimally deliver
6. To increase viscosity
the active pharmaceutical agent at the targeted
7.
To promote corneal/conjunctival adherence of
site in eye. The composition of formulations is active ingredient
designed in a way that allows easy administration
8. To increase corneal drug permeation
and effective drug bioavailability into the ocular
tissue with least amount of ocular irritation and 9. To increase solubility
toxic effects. It is desirable that ophthalmic 10. To stabilize the active ingredient and prevent its
decomposition
preparations are free from foreign particles and
microorganisms, have suitable pH, tonicity and
viscosity. Moreover, the preparations should be
stable and must have adequate shelf-life. EXCIPIENTS IN OPHTHALMIC
To achieve these properties in an ophthalmic
PREPARATIONS
formulation, appropriate selection of ingredients
other than the active pharmaceutical agent in Preservatives
appropriate quantities is of critical importance.1
These ingredients, known as excipients, are Treatment of various ocular diseases often requires
inactive, biodegradable and non-irritant. The patients to use topical medication multiple times
commonly used excipients in ophthalmic a day for short-term or at times for prolonged
formulations include preservatives, vehicles, period. To ensure the protection against the risk of
tonicity agents, buffers, antioxidants and contamination with microorganisms, preservatives
surfactant (Table 5.1). The use of excipients to are added to all non-surgical, multiple use
impart color, odor or flavor is prohibited. topical preparations. Antimicrobial preservative
in a multi-dose ophthalmic product prevent the associated with ocular irritation, dry eyes, damage
patient from administering microbiologically to epithelial surface and other adverse effects. The
contaminated product in the eye. The main criteria severity of adverse effects due to preservatives
for selecting a preservative are: depends upon the type of preservative used,
a. It should be effective at a low concentration its concentration, frequency of use during the
against broad spectrum of organisms day and total duration of use. Various types of
b. It should be soluble in the formulation preservatives used in ophthalmic preparations are
c. It should be compatible with the drug listed in Table 5.2.
packaging components
d. It should be effective over the shelf-life. Detergent Preservatives
The US Pharmacopoeia Preservative
Effectiveness Test (PET) requires inoculation of Detergents interact with the lipid components
preservative containing solution with 106 colony of the microbial cell membrane and alter its
forming units/mL (CFU/mL) of Staphylococcus permeability. Due to membrane instability,
aureus, Pseudomonas aeruginosa, Escherichia cell contents leak out causing cell death. The
coli, Aspergillus niger and Candida albicans. preservatives in this group include quaternary
Each organism is tested separately. Following ammonium compounds like benzalkonium
inoculation on day 0, survivor count is done on chloride, alcoholic and phenolic compounds and
day 7, 14 and 28. To pass the PET requirement, centrimonium.
preservative should be able to produce 1-log Benzalkonium chloride (BAK): It is the most
reduction on day 7, 3-log reduction on day 14 and commonly used preservative in ophthalmic
no increase in survivor count from day 14 to day medications. It is highly stable at wide range
28. Fungi should show no increase in survivor of pH and temperature. It has a wide range of
count from day 0 to day 28. antibacterial activity and is highly effective in
Addition of preservatives also prevents combating the common microbes contaminating
biodegradation and prolongs the shelf- the ophthalmic solutions. In antiglaucoma
life of the preparations. Although addition medications it is used in a concentration range
of preservatives provides protection against of 0.004–0.02%. BAK breaks the cell-cell
microbial contamination, their repetitive use is junctions in corneal epithelium and enhances drug
Table 5.2 Classification of preservatives used in ophthalmic formulations
Preservative group Chemical class Examples

Detergent preservatives Quaternary ammonium Benzalkonium chloride,
compounds Polyquaternium-1, Centrimonium
Alcohols Chlorobutanol
Phenols Methyl/propylparaben
Oxidizing preservatives Mercurial Thimerosal
Carboxylic acid Sorbic acid
Amidines Chlorhexidine
Transient preservatives (oxidizing Stabilized oxychloro complex (SOC), Sodium perborate
agents)
Ionic buffered preservatives Combination of boric acid, zinc, sorbitol and propylene glycol
Chelating agents EDTA
Ophthalmic formulations and ocular drug delivery 67
penetration into the anterior chamber. However, the time required to produce toxic effects is
the effects of BAK are cumulative and, therefore, longer than that due to BAK. Chlorobutanol has
repeated use over a prolonged period causes only limited use because of its lower efficacy
damage to corneal epithelium. The damaging and instability when stored over extended period
effects of BAK on corneal epithelial cells are at room temperature. It permeates through
dose-dependent causing cellular apoptosis at polyolefin plastic containers.
concentration as low as 0.0001% and necrosis at Parabens: There are esters of p-aminobenzoic
higher concentration. On repeated use BAK also acid and are especially effective against yeast
disrupts the lipid layer of tear film. Therefore, use and moulds. They have a wide spectrum of
of medication containing BAK should especially antibacterial activity and are unstable at a high
be avoided in patients with deficient tear film or pH. Parabens have been used as preservative in
corneal epithelial abnormalities. Long-term use ophthalmic solutions, suspensions and ointments.
in antiglaucoma medications can result in toxic Propyl paraben is most commonly used. Their
inflammation of ocular surface. In patients with aqueous solubility is relatively low and they may
superficial inflammation or corneal abrasion, cause ocular irritation. Parabens permeate through
simple measure of stopping all topical medication polyolefin plastic containers.
can promote healing.
Polyquaternium-1 (Polyquad®) is a derivative of Oxidizing Preservatives
BAK and acts in the same way as BAK. Initially, it The oxidizing agents are small molecules that
was used in contact lens solutions. The significant penetrate the microbial cell membrane and interfere
difference in the action of polyquad® as compared with the cellular functions by reacting with
to BAK is that although, it affects bacterial proteins, lipids and DNA. Oxidizing agents are less
cells but is repelled by corneal epithelial cells. toxic to ocular surface as compared to detergents.
Therefore, repeated use is less likely to damage The examples include thimerosal, sorbic acid,
the ocular surface than BAK. However, polyquad® chlorhexidine. Transient acting preservatives
reduces the density of conjunctival goblet cells sodium perborate and stabilized oxychloro
and its long-term use decreases production of the complex (SOC) are also oxidizing agents.
aqueous layer of tear film. Thimerosal: It is a mercury containing
Centrimonium: It has its antibacterial action preservative that was used extensively in topical
similar to BAK. The toxicity of centrimonium to preparations and vaccines. However, it was found
ocular surface is also similar to BAK and includes to be a common cause of allergy and its use in
keratinization and inflammatory infiltrates at vaccines was associated with high incidence of
the limbus and within the conjunctival stroma autism. Because of the safety concerns, use of
and epithelium. Although, it is a component of thimerosal in over-the-counter drugs was banned
some artificial tear solutions, it is primarily used in 1998.
as softener in hair treatment solutions due to its Sorbic acid: It is a natural organic compound.
antiseptic and cationic surfactant properties. It is Potassium sorbate has fungistatic and limited
also used as a fermentation aid, a dispersant and antimicrobial properties. It has been used
as preservative in antifungal creams. in ophthalmic medications and contact lens
Chlorobutanol: It has a wide range of solutions. Its antimicrobial efficacy is poor and
antibacterial action but is less effective than BAK. it is used in combination with other preservative.
It does not have surfactant action like BAK but At certain concentrations, the products of sorbic
causes bacterial cell lysis by damaging the lipid acid oxidation are known to discolor some
component of cell wall. Similar to BAK, it causes hydrophilic contact lenses. It can also cause
corneal and conjunctival cell damage, however, allergic reactions.
Chlorhexidine and polyhexamethylenebiguanide forms. It is a broad spectrum antimicrobial
have a broad range of antibacterial action like system. The ocular surface toxicity caused by
BAK. Additionally they are effective against these preservatives is significantly less than the
Acanthamoeba. They have poor fungicidal action. traditional preservatives and is almost comparable
They have been used in contact lens solutions. to that caused by preservative-free artificial
Unlike BAK, they do not cause significant tears. This preservative system has been used in
alteration in corneal permeability or the tear film travoprost formulation.
stability.
Chelating Agents
Transient Preservatives
Chelating agents like disodium EDTA have the
These are the newer oxidative preservative ability to bind with divalent metallic ions. EDTA
systems. These compounds do not accumulate and is added to ophthalmic preparations to enhance
upon exposure to tears dissipate into constituents the antimicrobial action of other preservatives
already present in the tear film such as Na+, Cl–, like BAK. It does not cause significant cellular
O2, and H2O. They have high antibacterial activity toxicity, however, allergic dermatitis may occur.
but significantly less cellular toxicity as compared
to traditional preservatives. Vehicles
Stabilized oxychloro complex (SOC): It is also
known as purite, is a component of a wide variety Ophthalmic solutions are prepared by dissolving
of ophthalmic medications such as artificial the active ingredient in an appropriate vehicle.
tears and antiglaucoma drugs. It has a broad Purified water is the vehicle of choice for
antibacterial, antiviral and antifungal action. this purpose in topical preparations as all the
Chemically it consists of chlorine dioxide, major therapeutic agents are water soluble
chlorite and chlorate. SOC dissociates into water, salts. The commonly used salt forms include
oxygen, sodium and chlorine free radicals when hydrochloride, nitrate, sulfate and phosphate.
exposed to light. The chlorine free radicals cause Salicylate, hydrobromide and bitartrate salts are
glutathione oxidation and inhibit microorganism also used. For acidic drugs like sulfonamides,
protein synthesis leading to microbial cell death. sodium salts are used. Non-aqueous liquids are
rarely used as they cause ocular irritation and poor
Sodium perborate: It is used in artificial tear
patient acceptability.
solutions. It alters protein synthesis within
bacterial cells by oxidizing cell membranes and
inhibiting membrane-bound enzymes. After Excipients to Enhance Ocular
instillation in eye, it converts into hydrogen Bioavailability
peroxide and then to oxygen and water. Hydrogen
Ingredients, other than those used to dissolve
peroxide effectively kills microorganisms.
the active ingredient are added to ophthalmic
formulations to enhance the ocular bioavailability
Ionic Buffered Preservatives of drugs. Such vehicles can enhance ocular
This is a newer class of preservatives that acts bioavailability by:
in the same way as oxidizing preservatives. An i. Increasing the corneal residence time: Visco
example in this category is a combination of sity enhancers and mucoadhesives, phase
boric acid, zinc, sorbitol and propylene glycol. transition vehicles (in situ gelling system).
Following instillation, contact with cations of ii. Increasing the corneal permeability of drugs:
tears converts these components into inactive Penetration enhancers
Exicipients That Increase Corneal Table 5.3 Mucoadhesive performance of several

polymers
Residence Time
Adhesive substances Performance
Viscosity Enhancers and Carboxymethyl cellulose Excellent
Mucoadhesives Carbopol Excellent
A large number of vehicles are used in ophthalmic Carbopol and hydroxypropyl Good
cellulose
formulations primarily to increase the drug’s
corneal contact time either by increasing the Carbopol base with white petrolatum Fair
viscosity of solution and/or by promoting its Carbopol 934 and EX 55 Good
adherence to corneal surface. Viscosity enhancers Poly (methyl methacrylate) Excellent
increase the thickness of tear film, reduce the tear Polyacrylamide Good
drainage and allow the drug to stay on corneal Poly (acrylic acid) Excellent
surface for a longer period. This increases the Polycarbophil Excellent
drug’s bioavailability as the time for which drug Homopolymers and copolymers of Good
stays on corneal surface increases. Hydrophilic acrylic
high-molecular weight polymers are used as Gelatin Fair
viscosity enhancers in concentrations that Sodium alginate Excellent
produce a viscosity of 5–100 cps. Use of viscosity
Dextran Good
enhancers in suspensions prevents particle
Pectin Poor
sedimentation between uses. However, initial
Acacia Poor
resuspension becomes more difficult due to high
viscosity. Mucoadhesives are the high-molecular Povidone Poor
weight electrically charged polymers.They bind Poly (acrylic acid) crosslinked with Fair
sucrose
with the conjunctival and corneal mucin layer,
stabilize the tear film and prolong the stay of drug
on corneal surface. Mucoadhesive performance
of several polymers is summarized in Table 5.3.
Polymers depending upon their loading to thick layer of medication on the cornea and
capacity deliver drugs in a controlled manner deposits on eyelids. High viscosity also makes the
over a prolonged period. This helps to achieve sterilization by filtration more difficult. Physical
steady state concentration at target sites without properties of vehicle are determined by molecular
significant fluctuations as is the case with other size, molecular weight, viscosity and presence of
formulations that provide pulsed drug delivery. salts, divalent cations and anions. Some of the
The polymers in controlled drug delivery systems commonly used polymers are discussed below.
are used either in the reservoir form or the matrix Cellulose derivatives are hydrophilic polymers.
form. In the reservoir form, the polymer forms a The commonly used agents in ophthalmic
coat around the active drug containing nucleus. preparations include carboxymethyl cellulose
In the matrix type, active drug is homogenously (CMC) and hydroxypropyl methylcellulose
mixed with polymer and forms covalent or (HPMC). CMC is a viscosity enhancer but in
hydrogen bond with polymer molecules. addition, due to its anionic charge, it promotes
The polymers generally used as inactive mucoadhesion and stabilizes tear film. The
vehicles with the active ingredients in artificial tear mucoadhesive property of CMC is significantly
solutions help to improve tear film stability in dry higher than other vehicles. HPMC is also a
eye conditions. There are several disadvantages viscosity enhancer like CMC. It increases the
of adding the polymers especially in high- tear film wetting time and significantly increases
viscosity solutions such as blurred vision due ocular retention time.
Polyvinyl alcohol (PVA) is a water-soluble Cyclodextrins are used to improve the solu
viscosity enhancer and is commonly used in a bility and drug delivery to corneal surface. They
concentration of 1.4%. The increase in viscosity consist of a lipophilic center to incorporate the
by 1.4% PVA is only half to that of 0.5% CMC. lipid soluble drugs and adhere to corneal surface.
Besides its use in ophthalmic preparations to Outer surface is hydrophilic consisting of 6–8
enhance viscosity and corneal residence time, it glucose units, which help to stabilize the tear film.
is also used for the treatment of corneal epithelial White petrolatum (60%) and liquid mineral
erosions. It is nonirritating and promotes healing oil (40%) mixture is used as vehicle in ointments.
of abrasions. This molecular complex melts at body temperature
Polyvinylpyrrolidone (PVP) is a polymer and releases the active drug. Water-miscible agent
having an average molecular weight in the range lanolin is added sometimes, which allows water-
of about 25,000–40,000. It is a thickening agent soluble drugs to be retained in the ointment.
that increases the corneal residence time of active Ointments are retained for a longer period in the
drug. As a lubricating agent, it is used in the conjunctival sac as they are cleared very slowly by
treatment of dry eyes. It helps in solubilizing some tear drainage. The nonpolar oil base of ointments
drugs like chloramphenicol. Ocular irritation is readily absorbed by precorneal and conjunctival
due to drugs like oxymetazoline reduces in the tear film. This allows increased corneal contact
presence of PVP. It is also used as stabilizer in time and prolonged drug delivery.
some ophthalmic suspensions like mefenamic
acid suspension. Phase Transition Vehicles
Sodium hyaluronate is a high molecular
weight polymer. When added to ophthalmic These are liquids that are converted to gel form
solution it increases viscosity. Due to its high when instilled into the cul-de-sac. The polymers
viscosity, it stabilizes tear film. After instillation, like lutrol FC-127 and poloxamer 407 undergo gel
repeated blinking reduces viscosity, an effect formation in response to change in temperature,
known as ‘shear thinning’. This property of i.e. at 37°C on the ocular surface. Cellulose
sodium hyaluronate is advantageous as thinning acetate phthalate is a polymer that forms gel when
of the solution due to blinking prevents feeling its native pH of 4.5 rises to 7.5 after instillation in
of ocular irritation. Several studies have shown eye. Gelrite is a polysaccharide, low-acetyl gellan
that addition of sodium hyaluronate to ophthalmic gum. It gels in the presence of mono or divalent
solution prolongs the corneal residence time of cations normally present in tears. These gel
some drugs and improves their bioavailability. forming vehicles increase the corneal residence
Polyacrylic acids such as carbopol gels time of the drug and prolong the drug’s duration
are used in ophthalmic solutions to enhance of action. Xanthan gum, a heteropolysaccharide
corneal residence time of the drug. Enhanced is also used as phase transition vehicle to prolong
viscosity of polyacrylic acid containing solutions corneal residence time of drugs.
decreases by increased shear rate due to blinking
and eye movement. Reduced viscosity reduces Excipients that Increase Corneal
ocular irritation and provides better patient Permeability
acceptability. Moreover, polyacrylic acids are
Penetration Enhancers
good mucoadhesives at the ocular surface.
Polyionic vehicles like poloxamer 407 have Penetration enhancers act by temporarily increasing
been used to improve the delivery of lipophilic the corneal permeability for drugs. The alteration
drugs like steroids. Poloxamer has a lipophilic in corneal epithelial permeability occurs either due
nucleus, which helps to deliver the lipid soluble to changes in cell cytoskeleton and tight junctions
drug to corneal surface and hydrophilic end chains to allow better paracellular absorption or due to
that stabilize the tear film. interaction with lipid or protein components of cell
membrane to allow better transcellular permeation. without affecting the stability of solution. Majority
Chelating agents, preservatives, surfactants and of ophthalmic drugs are salts of weak bases and are
bile salts exhibit these properties but are associated stable at acidic pH. Instillation of acidic solution is
with corneal toxicity. generally without much stinging sensation if the
induced tearing quickly restores the pH of instilled
Tonicity Agents formulation equal to that of tears. The choice of
buffer system to be used is of critical importance
The ophthalmic solutions require adjustment in this regard. Preferably the buffer system should
of tonicity close to that of natural tears. The be of low-capacity so that it can maintain the acidic
tonicity of natural tears is equal to that of 0.9% pH of formulation for stability but upon instillation
saline. Generally, a range of 0.5 to 2% saline allows tears to neutralize it. High capacity buffers
equivalent tonicity is well tolerated by eye. resist the pH adjustment by tears and cause stinging
Most formulations aim to achieve 0.7 to 1.5% due to presence of acidic solution on ocular surface
saline equivalent tonicity. Commonly used for a longer period. The corneal endothelium is
tonicity agents are NaCl, KCl, dextrose, buffer much less resistant to damage by pH variations
salts, glycerin, propylene glycol and mannitol. as compared to epithelium. Therefore, the pH
Hypertonic solutions induce lacrimation causing adjustment of intraocular formulation is extremely
immediate dilution and enhanced drainage of the important. The commonly used buffers include
drug. Hypotonic solutions are sometimes used phosphate, borate and acetate.
in the treatment of dry eyes when the tonicity
of natural tears is abnormally high. Hypertonic Surfactants
solutions are used to relieve corneal edema.
Surfactants in low concentration are added
to increase the dissolution and dispersion
Buffers of substances like steroids in solution. They
The adjustment of the pH of the ophthalmic also improve the clarity of solution. Nonionic
formulation is necessary not only for patient comfort surfactants are preferred over ionic as they are
and safety but it also stabilizes the formulation, less toxic. Polysorbate 80 (Tween 80) is used in
improves solubility, enhances preservative action ophthalmic suspensions. Polyoxol 40 stearate
and increases bioavailability. The pH of normal and propylene glycol are used to solubilize
tears is 7.4. Therefore, it is desirable to have the a drug in anhydrous ointment. Some agents
same pH for ophthalmic formulations. However, prevent drug loss due to adsorption to container.
this is often difficult and some drugs precipitate at Other examples of surfactants include polyoxol
this pH and many are unstable. The pH is, therefore, 40, hydrogenated castor oil and cremophore EL
adjusted in a way that it is as close to 7.4 as possible (Table 5.4).
Table 5.4 Wetting and solubilizing agents used in ophthalmic formulations
Benzalkonium chloride Polyoxyl 50 stearate Polysorbate 80

Benzethonium chloride Polyoxyl 10 oleyl ether Sodium lauryl sulfate
Cetylpyridinium chloride Polyoxyl 20 cetostearyl ether Sorbitan monolaurate
Docusate sodium Polyoxyl 40 stearate Sorbitan monooleate
Nonoxynol 10 Polysorbate 20 Sorbitan monopalmitate
Octoxynol 9 Polysorbate 40 Sorbitan monostearate

Poloxamer Polysorbate 60
Antioxidants Physicochemical properties of drugs, such as

lipophilicity, solubility, molecular size and shape,
Antioxidants are added to ophthalmic formulations drug charge and degree of ionization, affect the
containing epinephrine and other oxidizing drugs. mechanisms and rate of transport. Lipophilic
They stabilize the formulation and prevent its drugs are transported through the transcellular
degradation. Sodium sulfite and metabisulfite are pathway, while hydrophilic drugs penetrate
used in a concentration of 0.3% in epinephrine through the paracellular pathway. The optimum
hydrochloride and bitartrate solutions. Other apparent partition coefficient in octanol/buffer
antioxidants used are sodium thiosulfate, ascorbic (pH 7.4) for corneal drug penetration was found
acid and acetylcysteine. to be in the range of 100 to 1000. The stroma is a
highly hydrophilic tissue, which mostly consists
of water. Due to a relatively open structure,
OPHTHALMIC DRUG DELIVERY
drugs with molecular size up to 500000 can
SYSTEMS diffuse through normal stroma. Tight junctions
are present in corneal endothelium but they are
Critical Barriers in Ocular not as tight as those in the epithelium. It was
Therapeutics estimated that drugs with molecular dimension
Topical instillation remains the first choice in up to about 20 nm can diffuse through normal
ocular drug delivery. However, due to the innate endothelium. In addition to the physical barriers,
protective structure of the eye the bioavailability ocular tissues contain metabolic enzymes, such as
of an instilled drug is generally low. The cornea esterases, aldehyde and keton reductases, which
forms a non-vascularized barrier, which is may degrade and reduce the efficacy of the drugs.
As a result of these anatomical and physiological
highly resistant to passive diffusion of ions and
constraints, after topical application, a major
molecules. It has a smaller surface area compared
fraction of the administered drug is lost by
to conjunctiva, which has a leakier epithelium
different mechanisms, resulting in very low
than the cornea. The conjunctiva not only acts
ocular bioavailability (Fig. 5.2). Systemically
as a protective covering but also functions as a
administered drugs also fail to achieve adequate
passive physical barrier.2 level in ocular tissue due to blood-ocular barriers.
The unique features of anatomical structures For transconjuctival influx and efflux,
and physiological barriers for permeation transporters such as P-glycoprotein, are known
and distribution in ocular tissue for topically to play an important role. There is a significant
applied drugs are represented in Figures 5.1 systemic absorption via lymphatic and blood
and 5.2. Relevant details are discussed in vessels. The lacrymal film secreted by the
Chapter 3. Despite all the inconveniences goblet cells of the conjunctiva not only cleanses,
of topical administration, this non-invasive hydrates, lubricates and serves as a defense
method continues to be a favored route of drug against the pathogens; but also, it involves an
administration in clinical practice. Thus, the additional obstacle to any drug penetration. The
development of topical ocular drug delivery lacrymal film is a dynamic fluid and undergoes
systems with advances to overcome these a constant renewal and, therefore, limits the
constraints currently represents a promising time of residence of the drugs on the surface
approach for the treatment of ocular diseases.3 of the eye.
Figure 5.1 Compartmentalized scheme of drug penetration across human cornea, conjunctiva, and
sclera into anterior and posterior segment of the eye
Topical drug delivery systems 2. Control the release of drugs.

3. Achieve a targeted delivery.
ocular drug delivery systems represent an Liquid and semiliquid forms are the most
approach to control and optimize the drug delivery commonly used ophthalmic drug delivery
to target tissues in the eye. An optimum topical systems. They are cheap, convenient to use and
ocular drug delivery system would be one which can be easily self-administered. However, these
can be delivered in eyedrop form without causing devices do not provide continuous drug delivery
blurred vision or irritation and, which would need over a prolonged period, which is possible with
no more than one to two applications each day.4 solid drug delivery devices that are comparatively
The three major goals in developing topical expensive and inconvenient at times. Patient
ocular drug formulations are: acceptability in general is higher for liquid and
1. Enhance the drug permeation. semiliquid preparations.
Figure 5.2 Constraints in topical ophthalmic drug delivery
Conventional Ophthalmic Dosage preservatives. Other excipients are added to

Forms5 enhance corneal penetration. Corneal penetration
enhancement can be achieved best by increasing
Aqueous solutions: Most ocular diseases are solution concentration, increasing corneal contact
treated with topical application of solutions time by adding viscosity enhancers, selection of
administered as eyedrops. A homogeneous drug with appropriate pKa and offering optimal
solution offers many advantages including the lipid solubility with the use of appropriate buffers.
simplicity of large scale manufacture. The factors The stability of ophthalmic solutions and
that must be taken into account while formulating other dosage forms determines the shelf-life and
aqueous solution include selection of appropriate expiration dating of the product. The drug product
salt of the drug substance, solubility, therapeutic is analyzed for physical (pH, osmolality, viscosity,
concentration required, ocular toxicity, pKa, the color and appearance of the product), chemical
effect of pH on the solubility and stability, tonicity, (assays for the active and degradation product and
buffer capacity, viscosity, compatibility with other preservative efficacy of the product and bioburden
formulation ingredients, choice of preservative, of all compounds) and microbiological parameters
ocular comfort and ease of manufacturing. throughout the shelf-life.
Generally aqueous ophthalmic solutions Suspensions: Suspensions form an important part
are manufactured by dissolution of the active of the ophthalmic dosage forms and offer distinct
ingredient and other inactive ingredients advantages. Hydrophobic ophthalmic drugs have
followed by heat sterilization or sterile filtration. limited solubility in water. Formulation of a sterile,
Sterility of solution is further ensured by adding preserved, effective, stable and pharmaceutically
elegant suspension is more complex and Packaging and Storage
challenging compared to conventional ophthalmic
solutions. Particle size of the active agent plays a The packaging of solutions and suspensions in an
key role in physical stability and bioavailability appropriate container is important in determining
of the drug product. The rate of sedimentation, the delivery of right amount of drug to the ocular
agglomeration and resuspendability are affected surface. Conventional eyedroppers deliver the
by particle size. Generally, the average particle drops of the size ranging from 50–70 µL. Newer
size is less than 10 mm. The most efficient packages deliver antiglaucoma medications in
method of producing such particle size is by the drops of the size 25–56 µL. Many ophthalmic
dry milling. Other methods of particle size medications are now dispensed in bottles with
reduction include micro-pulverization, grinding, especially constructed dropper tip that allows
and controlled precipitation. An ophthalmic control over the volume of each drop delivered.
suspension contains many excipients such as These dropper tips consist of an outer chamber
dispersing and wetting agents, suspending agents, that delivers the drop connected with an inner
buffers and preservatives. The selection of buffers chamber through an aperture. The design allows
and preservatives for suspension are similar to only one drop to enter the outer chamber with
that of ophthalmic solutions in almost all aspects each squeeze. A change in the outer diameter
except that they must also be compatible with the and platform width allows desired changes in
flocculating systems.6 the size of drops. Many ophthalmic solutions are
The formulation of ophthalmic suspension now packaged in unit-dose dispensers to avoid
includes sterilization of the micronized active toxicity due to added preservatives in multi-dose
vials. The unit-dose dispensers contain about 0.1
drug either by dry heat, exposure to gamma
to 0.6 mL of the solution and as there is no added
irradiation or ethylene oxide or in some cases
preservative, they are for short-term use.
steam sterilization of concentrated slurry followed
Various ophthalmic solutions and suspensions
by ball-milling. Major steps of formulating an
are packaged in containers that do not differ much
ophthalmic suspension are: in size and shape. Therefore, it is important to
a. Preparation of a dispersion of the drug follow standardized labeling so as to facilitate
b. Preparation of the structured vehicle, followed clear identification of medications. Moreover,
by addition of the drug dispersion each time a medication is used the name on the
c. Addition of the other adjuncts, and label must be confirmed. The recommended
d. Homogenization. color coding of various ophthalmic solutions
The advantages and disadvantages of using and suspension is shown in Table 5.6. It is also
solutions and suspension are listed in Table 5.5. important to look for the expiry date on the
Table 5.5 Advantages and disadvantages of solutions and suspensions

Formulation Advantages Disadvantages
Solutions •• Easy instillation •• Short corneal contact time
•• No interference with vision •• Contamination
•• Ocular irritation less than suspension/ •• Mechanical injury during instillation
ointment
Suspensions •• Easy instillation •• Require adequate shaking before use
•• No or minimal interference with vision •• Inconsistent drug delivery
•• Corneal contact time longer than solution •• May cause clogging of dropper tip
•• Ocular irritation
•• Contamination
•• Mechanical injury during instillation
label. The medications are not recommended can be applied to each eye on an alternating
for use after the expiry date as the ingredients schedule. This helps to minimize discomfort due
may break down leading to loss of efficacy to blurred vision. The discomfort can also be
or toxicity. Eye drops if stored in refrigerator avoided by applying the ointment to lid margins,
may have a prolonged shelf-life, although, the lashes and canthi.
degree of ocular irritation is not affected by Use of ointments provides prolonged corneal
cold storage. Application of cold eye drops may contact time as compared to solutions because
help some patients to ensure proper instillation. of two reasons.1 After application to inferior
Some ophthalmic preparations are better stored fornix, ointments also spread over lid margin,
in inverted position. This allows air bubbles lashes and surrounding skin depending upon
to escape on the top of the liquid and avoids the amount applied and extent of tearing due
interference by air bubbles while using the to irritation. The ointment that spreads over lid
medication. margin keeps on releasing the drug over cornea
Ointments: Ointments are a common form of and thus enhances the drug-corneal contact time.2
topical ocular drug delivery. They are applied The nasolacrimal drainage of ointments is slower
to inferior fornix with patient looking up and lid than that of solution, allowing drug to stay in
retracted. Alternatively, especially in children, contact with corneal surface for a longer period.
ointments can be applied with the help of a cotton Slower nasolacrimal drainage of ointments is also
bud to the lid margin, lashes, medial and lateral responsible for reduced systemic side-effects as
canthus. If the patient is required to use ointment compared to solutions.
in conjunction with solution, solution must be The ointment can be applied postoperatively
instilled first because once applied ointments do only if the corneal wound is tightly secured.
not allow the solutions to reach the precorneal The ointment can be used in the treatment of
tear film due to their waxy vehicle. Following superficial corneal ulcers involving only the
application, ointments melt at body temperature epithelial surface and with clean margins. Corneal
and release the components, which spread over ulcers with large flap-like overhanging margins,
cornea. The spread of thick layer of medication those with impending perforation and open
over cornea may cause blurred vision. Therefore, conjunctival lacerations should not be treated
ointments are preferably used at bed time to avoid with ointment due to the risk of entrapment of
the discomfort due to blurred vision. If a day-time the ointment.
application is required the amount instilled should A typical formulation (Table 5.7) of an
be kept at minimum. Additionally, the ointment ophthalmic ointment includes micronization
and sterilization of the active agent by dry
Table 5.6 Standard colors for drug labeling and heat, ethylene oxide irradiation or gamma
bottle caps irradiation. Antimicrobial preservatives like
chlorobutanol or parabens are dissolved in
Drug Class Standard Color a mixture of molten petrolatum and mineral
b-blockers Yellow, blue, both oil and cooled to about 40°C with continuous
Mydriatics and cycloplegics Red mixing to assure homogeneity. Sterilized and
Miotics Green micronized drug is then added aseptically to the
Carbonic anhydrase inhibitors Orange
warm sterilized petrolatum/mineral oil mixture
with continuous mixing until the ointment is
Nonsteroidal anti-inflammatory Grey
drugs
homogeneous. The ointment is then filled into
presterilized ophthalmic tubes.
Steroids Pink
Anti-infective agents Brown
Gels: Ophthalmic gels consist of gelling-agent
with high water binding affinity. Like ointments
Table 5.7 Formulation components for various dosage forms7
Component Solution Suspension Ointment Gel Oral/injection Insert
Drug * * * * * *
Drug carrier # # # # # #
Water * * - * * #
Buffer/acid and base * * - * * -
Preservative * * # * * -
Tonicity agent # # - # # -
Salts # # - # # -
Viscosifier # # - - # -
Bioadhesive agent # # - # # #
Phase modifier - - - * # -
Suspending agent - # - # -
Solubilizer # - - # # -
Permeation enhancer # # - # # #
Wax/petrolatum/oil - - - - - #
Cross-linked polymer - - * - - *
* Component is included or generally included in the formulation, # Optional
they melt at body temperature to release the strong non-covalent bonds with the mucin
components. The blurred vision is much less coating on the biological membranes and thus
as compared to ointments and they can be used remain in place as long as the mucin is present.
during the day-time. Pilocarpine and some Bioadhesive polymers are usually macromolecular
artificial tear preparations are available in gel hydrocolloids with numerous hydrophilic
form. functional groups. Most of the bioadhesives
used in drug delivery systems are composed
Nonconventional Ophthalmic Drug of synthetic mucoadhesives, including water-
Delivery Systems soluble polymers that are linear chains and water
insoluble polymers that are swellable networks
Polymeric Gels joined by cross-linking agents. Typically, these
polymers have high molecular weight molecules
Polymeric gels are classified into two distinct
(5000–10000 Da), which cannot cross biological
groups: preformed and in situ forming gels, both
membranes and include cellulosic components
of which improve bioavailability and decrease the
like sodium carboxymethyl cellulose (CMC),
side-effects induced by the systemic absorption
or polyanion bioadhesives like polyacrylic acid
of topically applied ophthalmic drugs.
(PAA).
Bioadhesive Hydrogels: The efficacy of opht Hyaluronic acid (HA) is a high molecular
halmic semisolid hydrogels is mostly based weight biological polymer consisting of linear
on an increase of ocular residence time, via polysaccharides present in the extracellular
enhanced viscosity and mucoadhesive properties.8 matrix. In the eye, HA is present in the vitreous
Bioadhesive polymers are capable of forming body and in low concentrations in the aqueous
humor. HA has been shown to be a potent is raised to the eye temperature (33–34°C)
mucoadhesive polymer. Some investigations from a critical temperature (16°C). Cellulose
with the use of exogenous HA had led to the acetophtalate (CAP) is a polymer with potentially
characterization of this compound as a topical useful properties for sustained drug delivery to the
pseudoplastic polymer that guarantees a better eye. Latex is a free running solution at a pH of
protection of the cornea. 4.4, which undergoes coagulation when the pH is
With viscous Newtonian systems, the viscosity raised by the tear fluid to pH 7.4. In situ activated
is independent of the shear rate. With increasing gel-forming system has also been used with gellan
viscosity, beyond a limit, there is no further gum, an anionic extracellular polysaccharide,
increase of the residence contact time and secreted by Pseudomonas elodea. Gellan gum
blinking becomes painful. On the other hand, non- (Gelrite) formulated in aqueous solution, forms
Newtonian formulations that display pseudoplastic clear gels in the presence of mono or divalent
properties can acquire a viscosity decrease with cations typically found in the tear fluids.
increasing shear rate by blinking and ocular To reduce polymer content, a combination of
movement. Shear rates associated with normal polymers, methylcellulose or HPMC and carbopol
blinking are quite important (ranges from 0 s-1 at may also be used. The former polymers exhibit
rest to 10000 s-1 during blinking). Pseudoplasticity thermal gelation and the latter pH-dependent
is thus interesting because it offers significantly gelation. The formulation thus formed is an easy
less resistance to blinking and shows much greater flowing formulation, which reversibly forms a
acceptance than viscous Newtonian formulations. gel in a sol-gel transition between 25 and 37°C,
Moreover, it is widely accepted that such non- as well as with a pH increase from 4 to 7.4. A
Newtonian vehicles as HA, and polyacrylic acids possible mechanism of the thermal effect could
are more effective than Newtonian formulations be a decrease in the degree of hydration of
containing polyvinyl alcohol or cellulose in a methylcellulose and a conformational change
similar viscosity range. Furthermore, viscosity of the polymer structure with the increase in
and rheological behavior are not the only factors temperature. The acidic solution of polyacrylic
to be considered. Mucoadhesive and wetting acid can transform into a gel upon an increase in
properties are also critical parameters to take into the pH by the buffering action of tear fluid.
consideration during ophthalmic formulation.
In situ activated gel-forming systems: This can be Colloidal Systems
described as viscous liquids that upon exposure to A liquid retention drug delivery system, can be
physiological conditions will shift to a gel phase. represented by a colloidal system containing
The principal advantage of this formulation is drug in carrier. Colloids consist of small particles
the possibility of administering accurate and ranging in size from 100–400 nm suspended
reproducible quantities, in contrast to already in aqueous solution. Particle size above 10 µm
gelled formulations and promoting precorneal gives a foreign body sensation. The particles
retention. Three methods have been employed to consist of polymer complexed with the drug.
cause phase transition on the eye surface: change Colloidal carriers act by increasing the specificity
in viscosity can be triggered by a change in of the action of drugs towards a specific target,
temperature, pH, or electrolyte composition.9-12 . facilitate the bioavailability of drugs through
Sustained drug delivery can be achieved by biological membranes and protect a drug against
use of a polymer that changes from sol to gel at enzyme inactivation. Corneal epithelial cells
the temperature of the eye. The poloxamers are take up the particles by endocytosis and act as
polyols with thermal gelling properties. Their reservoir from which the drug is slowly released
solution viscosity increases when temperature in the surrounding tissue. Thus the need to
incorporate a viscous medium is eliminated. negative and neutral surface charge. Retention
These preparations are easy to administer and of liposomes on the corneal surface perhaps
require less frequent administration. Colloidal represents the major challenge for effective ocular
forms include liposomes, nanoparticles, niosomes, drug delivery. Several studies, have shown that
microemulsions, etc. introducing a positive surface charge on vesicles
can prolong precorneal retention time, enhance
Liposomes: These are the more recent additions
ocular bioavailability and ultimately increase
to drug delivery systems in ophthalmology.
the duration of pharmacological effect. This may
They offer a promising avenue to fulfill the need
be attributed to the ability of liposomes with a
for an ophthalmic drug delivery system that
positive surface charge to have a more stable
has the convenience of a drop, but will localize adsorption because corneal epithelium is thinly
and maintain drug activity at its site of action. coated with negatively charged mucin.
Liposomes are microscopic vesicles composed of Another strategy used to retard the precorneal
membrane-like lipid bilayers surrounding aqueous drainage rate of liposomes has been to coat
compartments. They can be multilamellar, small vesicles with mucoadhesive polymers. Liposomes
unilamellar and large unilamellar vesicles dispersed in carbopol solutions demonstrated
depending upon the number of lipid layers significantly enhanced precorneal retention
and size. The phospholipids used in lipid compared to non-coated vesicles. This was only
bilayer are phosphotidylcholine, phosphotidic observed in preparations at pH 5.0 and not at pH
acid, sphingomyeline, phosphotidylserine and 7.4. Decreasing the pH of the coated vesicles
cardiolipine. The drug, depending on its solubility to 5.0 has been shown to change the initial and
characteristics, will be incorporated into either basal drainage rates such that there is significant
the aqueous compartment or the lipid layer. increase in precorneal retention. The enhanced
Thus, liposomes can entrap both hydrophilic precorneal retention may result from the binding
and lipophilic compounds, so that it is possible of polymer to the mucin. At pH 5 the adhesion is
to apply water-insoluble drugs in a liquid greater possibly due to protonation of the carboxyl
dosage form. Because of the nature of the groups, thereby permitting hydrogen-bonding
components used for their preparation, liposomes
between the polymer and the mucin layer.
are biocompatible and bioerodible vesicles.
Since the cornea has been shown to have poor
Liposomes are more suitable for lipophilic drugs
endocytic activity, other proposed mechanisms
because hydrophilic drugs tend to leak out quickly
by which liposomes interact with cells such as
from the lipid enclosure. The storage stability
lipid exchange, contact release, adsorption and
of liposomes is poor. In some cases, liposomes
fusion, may predominate. Consequently, the rate
have been shown to improve efficacy, reduce
and extent of drug release from the vesicles may
toxicity, prolong activity and provide site-specific
be an important prerequisite for drug absorption
delivery. Liposomes may not only offer a means
at precorneal sites, particularly the corneal
to reformulate established drugs but also represent
epithelium.
a novel dosage form, which can be used for new
therapeutic entities unsuitable for traditional Nanoparticles: Nanoparticles are polymeric
dosage form development.13 colloidal particles ranging in size from 10 to
Biodisposition and pharmacological studies 1000 nm. They consist of macromolecular
have demonstrated that vesicles carrying a materials, in which the drug is dissolved,
positive surface charge often outperform vesicles entrapped, encapsulated, and/or to which the drug
with a neutral or negative charge. In vitro is adsorbed or attached.They can be classified
studies have shown that binding of liposomes into two groups: nanospheres and nanocapsules.
to the cornea decreased in the order of positive, Nanospheres are small solid matricial spheres
consisting of dense solid polymeric network. stabilize the interfacial area. They have a
Drugs can either be incorporated in the matrix transparent appearance, thermodynamic stability
of the nanospheres or adsorbed onto the surface and a small droplet size in the dispersed phase
of the colloidal carrier. Nanocapsules are small (< 1.0 mm). Microemulsions are an interesting
capsules with a central cavity (oily droplet) alternative to topical ocular drug delivery,
surrounded by a polymeric membrane. Various because of their intrinsic properties and specific
polymers can be used to fabricate nanoparticles structures; they can be easily prepared through
such as polyacrylamide, polymethylmethacrylate, emulsification, can be easily sterilized, are
polylactic-co-glycolic acid and E-caprolactone. stable and have a high capacity for dissolving
All of these polymers are biodegradable and drugs. The administration of oil-in-water
undergo hydrolysis in tears. The drug polymer microemulsions could be advantageous, because
binding depends upon the physicochemical of the presence of surfactant and co-surfactant,
characteristics of both and determines the which act as penetration enhancers. Moreover,
rate of drug release. Nanoparticles are coated microemulsions achieve sustained release of a
with bioadhesive polymers like chitosan. This drug applied to the cornea and higher penetration
prolongs the stay of particles in the cul-de-sac into the deeper layers of the ocular structure
and corneal surface. Nanoparticles as drug and the aqueous humor than the native drug.
carriers for ocular delivery have been found Additional advantages of these systems include:
to be more efficient than liposomes and in low viscosity, a greater ability as drug delivery
addition to all positive features of liposomes, vehicles and increased properties as absorption
the nanoparticles are exceptionally stable and promoters. The possibility of prolonged release
the sustained release of drug can be modulated.14 of drugs in microemulsions makes these vehicles
very attractive for ocular administration and can
Niosomes: The niosomes are physically similar to
greatly decrease the frequency of application of
liposomes but the vesicle membrane is made up
eye drops. Besides this, the low surface tension
of nonionic surfactant. Niosomes are chemically
of microemulsions also guarantees a good
stable and entrap both the hydrophilic and
spreading effect on the cornea and mixing with
lipophilic drugs. Niosomes contain nonionic
the precorneal film constituents, thus possibly
surfactants, which are non-antigenic and non-
improving the contact between the drug and
toxic to the eye so they can be used over a longer
the corneal epithelium. Some of the developed
period of time.The bioavailability of hydrophilic
microemulsions also presented a viscosity value
drugs is better than liposomes as the surfactant
that allows sterile filtration and easy dispensing
also acts as penetration enhancer. Niosomes
as eye drops.
provide site-specific drug delivery for prolonged
period and are stable on storage.15
Other Drug Delivery Systems
Discomes: The discomes are similar to niosomes
but the particle size is larger (12–16 µm). Solulan Cyclodextrins
C24 is the nonionic surfactant used. They are
The pharmaceutical use of cyclodextrins (CD)
retained in the cul-de-sac and are poorly drained
is confined mainly to the complexation of
into the systemic circulation due to large particle
problematic drugs (poorly soluble, unstable,
size. They provide prolonged drug release of
irritating, and difficult to formulate substances).
hydrophilic drugs.16
CD complexation generally results in improved
M i c r o e m u l s i o n s : M i c r o e m u l s i o n s a r e wettability, dissolution, solubility, stability
dispersions of water and oil that require surf and reduced side-effects.17 CDs are a group
actant and co-surfactant agents in order to of homologous cyclic oligosaccharides with a
hydrophilic outer surface consisting of six, seven tear fluid, swells and is converted to a gelatinous
or eight glucose units. Although soluble in water, mass. This gelatinous mass keeps on releasing
CDs have a lipophilic cavity in the center. They the polymer over 24 hours. Lacrisert is useful
form inclusion complexes with many lipophilic in the treatment of moderate to severe dry eyes.
drugs by taking up a drug molecule, or part of Some amount of basal tear secretion is necessary
it, within the lumen, resulting in an increase for lacrisert to act and in eyes with absolute tear
in solubility. The first cyclodextrins studied, deficiency lacrisert fails to provide therapeutic
had relatively low aqueous solubility and were benefit. Although, once a day application provides
shown to cause hemolysis and nephrotoxicity, sufficient relief of symptoms, some patients
These cyclodextrins had only limited use. Among may require twice a day insertion. Lacrisert is
cyclodextrin derivatives, hydroxypropyl-fl-cyclo generally well tolerated and displacement of
dextrin has been shown to be the most favorable the device is uncommon. The most common
in the hemolysis study on human erythrocytes. problems encountered during its use are foreign
body sensation and blurred vision due to spread
Inserts of polymer over cornea.
A collagen shield is a soluble insert, which
Inserts can be erodible or non-erodible. They have offers the advantage of being entirely soluble so
proven long duration of release and ability to that it does not need to be removed from its site
modify drug bioavailability when compared with of application, thus limiting the interventions to
their solution dosage forms. Although, inserts insertion only. Collagen shields are made up of
have shown therapeutic success, they are not well porcine or bovine scleral collagen. They are thin
tolerated by patients, and considering their high membranes ranging in diameter from 14.5–16
cost per dose, are not perceived as desirable next- mm. The water content varies from 63–85%.
generation topical ocular drug delivery systems.18 They are packaged as dehydrated shields. Before
Ocusert® (Alza Corporation) is an insoluble insertion they are soaked for about 3 minutes in
ophthalmic insert classified in the group of saline, lubricant or drug solution. The rehydrated
diffusional systems. It consists of a central shield upon insertion takes the shape of cornea.
reservoir of drug (e.g. pilocarpine) enclosed Initial insertion may be uncomfortable and may
between two semipermeable membranes, which require use of a local anesthetic. Following
allow the drug to diffuse from the reservoir at a
insertion, collagen shields undergo dissolution by
precise rate for a period of 7 days. Prolonged
the enzymes in tear film and release the drug on
reduction in intraocular pressure was achieved
ocular surface. Dissolution time depends upon the
with a single Ocusert® in patients with open-angle
amount of cross-linking in its material and varies
glaucoma. Because of the insolubility of the
from 12–72 hours for different preparations.
Ocusert® device, it must be removed after use.
The oxygen permeability of collagen shields is
The inserts were well tolerated but after prolonged
comparable to that of hydroxyethyl methacrylate
wear they tend to swell and partially fragment.
lens of similar water content.
Now it is recommended that they not be worn
for more than 12 hours, despite the potential for For conditions requiring prolonged drug
prolonged release over several days. delivery to ocular surface collagen shields are more
Lacrisert is a solid artificial tear preparation effective, convenient and safe devices as compared
measuring about 1 mm in width, 4 mm length to multiple daily eye drops, daily subconjunctival
and contains 5 mg of hydroxypropyl cellulose injections or soft contact lenses. However, collagen
without preservative. It is packaged in dehydrated shields are expensive and are available in a limited
form and with the help of an applicator is inserted number of base curves and diameters, which may
into the inferior fornix. After insertion it imbibes not be suitable to fit on all corneas. They can
cause foreign body sensation and allergy. Using the cornea, non-irritant, and able to release the
collagen shields to deliver a combination of drugs parent drug within the eye at a rate that meets
may be problematic due to drug-drug interactions. therapeutic need.
They should be used with caution in patients with
compromised corneal endothelium and cases of POSTERIOR SEGMENT DRUG
significant chemical burn.
DELIVERY SYSTEMS
Prodrug (Chemical Delivery System) Iontophoretic Devices
Use of prodrug molecules of some drugs allows Numerous iontophoretic devices with different
better corneal drug permeation. It also gives capabilities are commercially available. The most
selective and site-specific drug delivery. Some basic of these units consist of two electrodes, a
of the drugs used in prodrug forms include power source, timers, and an ampere meter for
epinephrine, phenylephrine, albuterol. Soft- measuring current output. As iontophoresis is not
drugs, unlike prodrugs, are active drugs, which entirely without risks, efforts are continuously
are designed to undergo a predictable and made to develop systems that can substantially
controllable deactivation in vivo. An example of reduce, if not eliminate, any risk of injury caused
ophthalmic application of the soft-drug approach by use of the device. The systems discussed
is metoprolol. If the prodrug approach is applied to below represent a small sampling of those
a soft-drug the resulting drug is known as a ‘pro- available.
soft drug’. A chemical delivery system (CDS) or
site-specific CDS is an inactive drug derivative,
Coulomb Controlled Iontophoresis (CCI)
which undergoes several predictable enzymatic
transformations via inactive intermediates The amount of drug delivered by iontophoresis
and finally delivers the active drug to the site depends on the current density, duration of
of action. Ophthalmic applications of a CDS treatment, drug concentration, pH, and the
include adrenolone esters (CDS of adrenaline), permeability of the tissue for the drug molecule.
propanoloneoxime (CDS of propanolol) and As current is being applied, the damage to tissues
alprenoxime (CDS of alprenolol). caused by heat may affect the hydration level of
Prodrugs were introduced in ophthalmology the tissue. With time, the resistance may change in
about 30 years ago when ocular absorption the damaged tissue, resulting in variable electrical
of epinephrine was substantially improved fields. Thus, the iontophoretic character of the
by its prodrug, dipivefrine. Currently, it has drug being applied changes with time. The CCI
replaced epinephrine in the treatment of elevated system was developed to avoid these problems.20
intraocular pressure associated with glaucoma. The CCI iontophoretic system produces and
Since dipivefrine, numerous prodrugs have been maintains a constant electrical field across the
designed to improve the efficacy of ophthalmic conjunctival epithelium, allowing a constant drug
drugs, to prolong their duration of action and/ flow (i.e. electrical current) during transscleral
or to reduce the systemic side-effects. Prodrugs iontophoresis. The ability of the CCI system to
have been tested experimentally and clinically automatically adjust to changes in resistance is a
but stability and solubility problems as well as major advantage over other iontophoretic delivery
local irritation after topical application have methods. Poor probe contact or disruption of the
limited their efficacy and clinical acceptability.19 circuit is indicated by an audio-visual alarm, and
An ideal ocular prodrug should be stable and the instrument continuously records the total
soluble in aqueous solutions to enable formulation, Coulombs delivered, thus ensuring a calibrated
sufficiently lipophilic in order to penetrate through and controlled delivery of drug.
Mini-ion Iontophoretic Unit the human sclera by an electrical field.23 The

sclera has many microscopic to molecular-scale,
The mini-ion device is portable and can be water-filled pores. The pores in the sclera are large
operated by battery or external electrical source. enough for nucleic acids to wander through under
The mini-ion device applies a variable electrical the influence of an electrical field.
current in the range of 0.1–1.0 mA for preset
periods of 10–120 s. The device uses a disposable
drug-loaded hydrogel probe to safely deliver
Scleral Implants
doses of charged drugs to different segments of Sustained release scleral implants provide
the eye following transscleral iontophoresis.21 controlled drug release that is achieved by a
polyvinyl alcohol membrane.It has been observed
Eyegate that in terms of the drug release profile, an implant
with a non-biodegradable polymer membrane is
The Eyegate iontophoresis device/applicator is more controllable than one using a biodegradable
made of medical grade, soft silicone rubber and is polymer. Since non-biodegradable devices could
designed to closely fit the human eye contour and release drugs over a longer period of time, these
palpebral conjunctival opening. The applicator has systems may be well suited for the treatment of
an annular shape; the diameter of the proximal part chronic ocular diseases, such as age-related macular
is slightly larger than the limbus, while the distal degeneration and diabetic retinopathy.24 This
part covers 2 mm of the anterior sclera behind the system may be more useful than the intravitreal
limbus. The annular well of the device (0.5 cm3) drug delivery systems in delivering the drug more
contains a pure tungsten electrode immersed in the effectively to the macular region without increasing
solution.22 The drug solution is infused into the drug concentration in the aqueous humor and site-
applicator via two silicone tubes, one of which is specific treatment in the retina-choroid.
a drainage tube that generates a slight suction to
maintain the applicator in perfect contact with the
conjunctiva and ensures a constant flow of drug
Transdermal Systems
inside the cup. Vanes located between the walls Transdermal therapeutic systems (TTS) enable
prevent the electrode from touching the eye, but one to avoid the peaks and valleys in the drug
allow drug contact with the conjunctiva and sclera plasma levels that occur with oral dosing. Large
(fluidic surface of 0.5 cm2). The drug solution does variations in the plasma levels of any drug
not cover the corneal surface and vision is not may cause unwanted side-effects. A new TTS
impaired during treatment, which makes treatment for delivery of ocular drugs has been reported
more comfortable for the patient. for prednisolone.25 The results suggested that
the prednisolone-TTS was more effective than
Electrical Fields conventional topical or oral administration.
Furthermore, the ocular bioavailability and tissue
The basis of electrophoresis, electroporation, concentration profiles suggest that other ocular
or iontophoresis is the use of an electrical field hydrophobic drugs similar to prednisolone may be
to enhance delivery of substances into and/or amenable to TTS delivery. Thus, TTS delivery of
across support media, cell membranes or tissues. ocular drugs may be a safe and effective method
The DNA and RNA, being hydrophilic and for treating chronic posterior segment diseases.
highly charged at neutral pH, would be ideal
molecules for enhanced ocular drug delivery by
Photodynamic Therapy
electrical fields. It has been demonstrated that
small RNA or DNA (up to 8 million Daltons) Photodynamic therapy plays an important role
synthetic oligonucleotides could be driven across in the treatment of neovascular age-related
macular degeneration. The method requires Extraocular Irrigation
intravenous administration of a photosensitive
dye, verteporfin. The dye accumulates in the Extraocular irrigation with copious amount
neovascular tissue and is activated by exposure of fluid is required in the treatment of acute
to non-thermal light at 689 nm. This activation chemical burns, to remove foreign body, dye or
generates free radicals, which cause cell death and viscous fluid used in gonioscopy. With patient in
occlusion of abnormal new vessels. The method supine position and head tilted towards the side
helps in destroying the neovascular tissue with to be irrigated, extraocular irrigation fluid at room
minimal or no damage to normal vasculature. temperature is delivered to the surface of eye from
a simple container. The fluid flowing out of the
eye is removed or collected in tissue, towel or
MODES OF ADMINISTRATION a collecting pan. The method is easy to use and
OF TOPICAL OPHTHALMIC cost-effective but requires an attendant to carry
FORMULATIONS out the irrigation. For patients who require long-
term irrigation and especially those who are not
The most common route of drug administration ambulatory, continuous irrigating system is used.
in ophthalmology is by topical application and, This irrigation system consists of a polyethylene
therefore, several modes of topical application tube, which is inserted through the lid and is placed
are in use. Instillation of liquid ophthalmic in lower fornix. The other end of tube is anchored
formulations is the most commonly employed to the skin by stitches or tapes and connected with
method. The method of topical instillation an overhead reservoir, from which fluid flows into
is described in Chapter 2. The modes of the eye. The flow can be controlled with the help
topical administration other than instillation are of an adaptor attached to tubing. The system is
described here. usually well tolerated with no apparent discomfort.
In cases where lid penetration by tubing is not
Sprays desirable, other measures such as loops, rings,
tubes and heptic contact lens shells are used.
Sprays are the alternative method of delivering
ophthalmic solutions to eye. They are less
Lid Scrubs
irritating than solutions. The spray device is
held at a distance of 5–10 cm from eye and the Lid scrubs consist of solutions and ointments
lid margins of gently closed eyes are sprayed. applied directly to lid margins with the help of
Subsequently, patient is asked to blink several a cotton-tipped applicator. Baby shampoo or
times over 10–15 seconds. A stinging sensation is other eyelid cleansers are used to clean the lid
an indicator of the presence of drug in precorneal margins in contact lens users or to remove oil,
tear film. If no stinging sensation is experienced debris and desquamated skin in inflamed eye.
a second application is required. Use of lid scrubs is especially helpful is cases of
Mydriatic and cycloplegic combinations such blephritis and the efficacy is better as compared
as phenylephrine-tropicamide or phenylephrine- to instillation of drops or ointment in the inferior
fornix. Antibiotics can also be used as scrubs. The
tropicamide-cyclopentolate can be used in the
commercial preparations available as lid scrubs
form of spray. Their efficacy is as good as that of
should not be instilled directly into the eye.
solutions and risk of contamination is negligible.
Application with eyes closed allows only minimum
quantity to reach the precorneal tear film. Ocular Filter Paper Strips
irritation is less and patient acceptability is high Ophthalmic dyes such as fluorescein sodium,
especially with pediatric patients. rose bengal and lissamine green are available
as drug-impregnated filter paper strips. The of drug are complementary to each other, better
strips are moistened with a drop of saline or drug permeation occurs. Lenses with high water
extraocular irrigating solution and are touched content absorb higher amounts of water soluble
with the superior or inferior bulbar conjunctiva drugs. Thicker lenses absorb and store greater
or inferior fornix. The method allows easy amount of drug whereas thinner lenses allow
administration of adequate amount of drug. greater amount of drug to enter precorneal tear
Administration of excessive quantity of drug film. Higher concentration of soaking solution
is avoided. Importantly, the methods helps in and longer soaking time allows greater drug
avoiding contamination due to use of solution permeation into the lens. The efficacy of soft
especially the risk of contamination of sodium contact lenses as drug delivery devices has
fluorescein with Pseudomonas aeruginosa is been found to be as good as subconjunctival
eliminated. Separate filter paper strips should be injections. Use of hydrogel contact lenses
used for two eyes to avoid cross-contamination. in conjunction with ophthalmic solutions
containing benzalkonium chloride has also been
Cotton Pledgets found to be clinically acceptable.
Cotton pledgets are thin and elongated cotton

bodies. They are soaked in ophthalmic solution REFERENCES
and placed in inferior fornix. Prolonged drug
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ophthalmic solution are efficient devices
6. Bapatla KM, Hecht G. Ophthalmic ointments
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ChapteR 6
Mydriatics and Cycloplegics
OVERVIEW of accommodation and stimulation of tear

secretion.
Mydriatics and cycloplegic drugs, both dilate Cholinergic receptors in sphincter and ciliary
the pupil (mydriasis). Additionally, cycloplegics muscle are of muscarinic type with predominance
paralyze the ciliary muscle and cause loss of of M 3 subtype. 3 Sympathetic input to eye is
accommodation (cycloplegia), i.e. inability to focus relatively small as compared to parasympathetic
on the near objects. Mydriatics and cycloplegics input and maintains a persistent tone in dilator
are widely used drugs in ophthalmology for muscle, aiding relaxation of the sphincter and
diagnostic and therapeutic purposes. pupillary dilatation. The time course of the
sympathetic responses is slower as compared to
parasympathetic responses and takes about 30–40
MECHANISM OF ACTION seconds to reach the peak effect. Parasympathetic
responses reach the peak effect within 1–2
The diameter of pupil is controlled by two sets of seconds.
muscles: dilator pupillae and sphincter pupillae. Sympathomimetic drugs cause contraction of
The dilator pupillae consists of radial fibers and radial fibers of dilator pupillae and, thereby, cause
is innervated by sympathetic nervous system. mydriasis. Sympathomimetic drugs have little
The adrenergic receptors in the dilator pupillae effect on accommodation and light reflex remains
are mainly α and a few β (β2-receptor subtype). intact. Sympathomimetics also affect the width
Sympathetic control of ciliary muscle action is not of palpebral fissure, diameter of ocular blood
well established. However, there is some evidence vessels and aqueous flow. Cholinergic antagonists
that sympathetic stimulation of ciliary muscle act by blocking the muscarinic receptors, which
antagonizes accommodation in human eye.1-2 are present on both the sphincter pupillae and
Sphincter pupillae consists of circular ciliary muscle, thereby, producing pupillary
fibers and is innervated by parasympathetic dilatation and paralysis of accommodation.
(cholinergic) nerves. Parasympathetic nerves Sympathomimetics are comparatively weak
also innervate ciliary body and lacrimal glands. mydriatic agents and in people with an iris difficult
Therefore, parasympathetic activation causes to dilate, such as diabetics or blacks, stronger
not only the contraction of sphincter muscle antimuscarinic agents are used. Mydriatics can
leading to pupillary constriction but also causes raise the intraocular pressure and can precipitate
ciliary muscle contraction leading to spasm glaucoma in predisposed individuals.
USES: DIAGNOSTIC AND Table 6.1 Indications for the use of mydriatics for
diagnostic purposes
THERAPEUTIC
1. Sudden decrease in visual acuity
Mydriatics and cycloplegic drugs are primarily 2. Unexplained loss of visual field
used to 3. Diabetes mellitus
1. Facilitate ophthalmoscopic examination of the
4. Symptoms of floaters, photopsia,
lens periphery, vitreous and retina. metamorphopsia, spots, shadows
2. Paralyze the ciliary muscle in young patients
5. Ocular pain in the absence of elevated
as an aid for refraction. intraocular pressure (IOP)
3. Dilate the pupil and paralyze the ciliary
6. Red eye that can not be attributed to infection,
muscle in uveitis; to prevent formation of allergy of elevated IOP
synechia and relieve the symptoms of pain 7. Recent blunt ocular trauma (except when
and photophobia. hyphema is present)
When used for diagnostic purpose, mydriatics 8. Myopia > 6D or when degenerative changes
allow examination of small details, which are present
are of great diagnostic importance such as 9. Media opacities making posterior segment
diabetic microaneurysms, hypertensive arteriolar examination difficult
attenuation, small retinal holes and other peripheral 10. Retinal diseases, detachment, tears
lenticular and retinal lesions. A reasonably good
11. Vitreous hemorrhage
examination of optic disc and retinal vessels
can be performed through an undilated pupil 12. Peripheral lenticular opacities
especially in young adults with spontaneously
large pupils but in elderly patients dilatation is Table 6.2 Contraindications for the use of mydriatics
frequently required. Moreover, the risk of missing
1. A known or suspected case of angle closure
an important diagnostic finding by failing to dilate
glaucoma
is more than the risk of precipitating glaucoma
2. Abnormally narrow anterior chamber angle
by dilating the pupil. Therefore, it is important to
perform mydriasis in appropriate cases and it is a 3. Active corneal disease
moral and legal duty of the optometrists to refer 4. Iris fixation lens pseudophakia
the pathological conditions for medical attention. 5. Hyphema
Some of the indications and contraindications for 6. Suspected penetrating ocular injury
the use of mydriatics are listed in Table 6.1 and 6.2. 7. Conditions when pupil reactions need to
be preserved such as head injury, recent
neurological anomalies, iris trauma
COMMONLY USED MYDRIATICS AND 8. Known hypersensitivity to a mydriatic drug
CYCLOPLEGICS
The mydriatics and cycloplegics commonly used
in clinical practice are: It causes contraction of dilator pupillae causing
pupillary dilatation, constriction of conjunctival
1. S y m p a t h o m i m e t i c s : P h e n y l e p h r i n e ,
hydroxyamphetamine. vessels causing blanching and contraction of
2. Antimuscarinic: Atropine, homatropine, Muller’s muscle causing widening of palpebral
hyoscine, cyclopentolate, tropicamide. aperture. 4,5 The effect of phenylephrine on
accommodation is relatively weak . It is available
in single-use units in concentrations of 2.5 and
Phenylephrine
10%. As a mydriatic agent, higher efficacy of
Phenylephrine is an α-adrenergic agonist and is the 10% phenylephrine as compared to 2.5% is
only sympathomimetic mydriatic in clinical use. not established. However, higher concentration
mydriatics and cycloplegics 89
is more often associated with adverse effects.Ocular adverse effects: Local adverse effects
of phenylephrine include stinging, pain,
Following topical application, mydriasis begins
in about 10 minutes and reaches peak in 45–60 lacrimation and keratitis. Phenylephrine can
cause allergic dermatoconjunctivitis giving
minutes. The pupil returns to pre-instillation size
a scalded appearance around the eye. It can
in 6–7 hours. These times can vary significantly.
Diabetics dilate slowly and less widely as cause transient corneal edema. In elderly
compared to non-diabetics. Phenylephrine patients, phenylephrine causes rebound miosis
10% has shown significantly higher efficacy asand re-instillation at this time gives a slow
compared to 2.5% concentration in diabetics. response. Long-term repeated use results in
slow and less intense mydriasis. In elderly
People with dark iris tend to develop mydriasis
slowly but for a longer duration as the drug patients, phenylephrine has been shown to cause
release of pigment from iris, which appears as
binds to pigment in iris. It produces less effect
on accommodation as compared to muscarinic aqueous floater in about 30–40 minutes and
antagonists. disappears in 12–24 hours.8 Long-term use of
low concentrations as ocular decongestants also
In addition to its uses as mydriatic agent,
causes rebound conjunctival congestion.
phenylephrine is also used for other therapeutic
purposes. Phenylephrine causes blanching of Skin pallor due to cutaneous vasoconstriction
caused by over spilling phenylephrine 2.5%
superficial conjunctival blood vessels (whitening
of the eye) and in very low concentrations eye drops was reported in premature neonates.9
(0.125%), it is used as ocular decongestant. Blepharoconjunctivitis and dermatitis due to
In a concentration of 10% phenylephrine is phenylephrine eyedrops has also been reported.10
applied topically for breaking synechiae. 4 Systemic adverse effects: Phenylephrine 10%
has been shown to cause rise in mean arterial
Topical 10% solution is also used for peripheral
corneal vasoconstriction during LASIK blood pressure in dogs. 11 Elderly patients
surgery. Phenylephrine 2.5% in combination especially those with cardiovascular disease
with ecothiophate can be used to prevent the are prone to develop acute rise in blood
formation of miotic cysts in the treatment pressure following topical application of 10%
of open-angle glaucoma or accommodative phenylephrine.12 Neonates and insulin-dependent
diabetics with vascular disease and autonomic
estropia.6 The mechanism involved in prevention
of cyst formation is not known. Phenylephrine dysfunction also respond similarly to 10%
also causes widening of palpebral fissure by phenylephrine. 13,14 Other systemic adverse
stimulation of Mueller’s muscle and ptosis effects of 10% phenylephrine include occipital
resulting from sympathetic denervation such asheadache, ventricular arrhythmias, tachycardia,
in Horner’s syndrome may respond favorably. reflex bradycardia, subarachnoid hemorrhage,
Phenylephrine 1% is also used in the diagnosisruptured aneurysm, skin blanching.
of Horner ’s syndrome. 7 It causes marked Cardiovascular adverse effects of topical
10% phenylephrine can be potentiated in
pupillary dilatation in the eye with postganglionic
sympathetic denervation but minimal or no patients receiving tricyclic antidepressants and
monoamine oxidase inhibitors. Patients on
dilatation in normal eye. If the lesion is central
reserpine, methyldopa and guanethidine also show
or preganglionic, the pupil behaves in the same
way as in the normal eye. excessive pressor response to phenylephrine due to
denervation hypersensitivity. Phenylephrine 2.5%
is rarely associated with systemic adverse effects
Adverse Effects
and is recommended for routine clinical use. The
Topical use of phenylephrine may give rise to guidelines for the use of 10% phenylephrine are
local as well as systemic adverse effects. outlined in Table 6.3.12,14,15
Table 6.3 Guidelines for the use of 10% phenylephrine Adverse Effects
1. Use with caution in patients with cardiac disease, Topical use of hydroxyamphetamine for routine
hypertension, insulin-dependent diabetes mellitus, mydriasis causes little, if any, ocular irritation.
aneurysm, advanced atherosclerosis, idiopathic
orthostatic hypotension Due to its indirect action it is considered
a safer mydriatic in patients with shallow
2. Do not use more than one application per hour
in each eye anterior chamber.18 Systemic absorption of the
hydroxyamphetamine can cause rise in blood
3. Do not use in atropinized patients; this can
cause tachycardia and hypertension pressure, however tachyphylaxis develops for
4. Do not use in patients receiving tricyclic
this effect. It is also ineffective in patients with
antidepressants, monoamine oxidase inhibitors, postganglionic denervation. Because of these
reserpine, methyldopa and guanethidine reasons hydroxyamphetamine is safer than
5. Use only 2.5% solution in infants and elderly phenylephrine in patients with insulin-dependent
6. Prolonged irrigation/application and diabetes, idiopathic orthostatic hypotension and
subconjunctival injection is not recommended patients receiving reserpine, methyldopa and
guanethidine.
Hydroxyamphetamine Atropine
Hydroxyamphetamine is an indirect acting Atropine is a naturally occurring alkaloid obtained
sympathomimetic. It acts by stimulating the from the plant Atropa belladonna (deadly
release of norepinephrine from adrenergic nightshade). It was the first antimuscarinic used
nerve terminals. Topical instillation of 1% in medicine and is the most potent mydriatic-
solution causes pupillary dilatation and also some cycloplegic drug. It is a non-specific muscarinic
vasoconstriction. It has no significant effect on antagonist that acts by competitively inhibiting
accommodation and refractive state.16 It is used the actions of acetylcholine. It acts both centrally
only as a mydriatic agent. The time of onset of and peripherally. It is available commercially as
mydriasis and the time to reach the peak effect is sulfate derivative in 1% solution or 1% ointment
comparable to phenylephrine 2.5%.17 However, formulation.
the maximal dilatation may not be adequate Topical application results in persistent
especially in diabetics to examine peripheral mydriasis unresponsive to light and cycloplegia.
retinal abnormalities. To achieve greater pupillary Following application of single drop of 1%
dilatation, it is used in combination with a solution, mydriasis begins in about 10 minutes
muscarinic antagonist such as tropicamide 0.25%. and reaches peak in 25–30 minutes. It starts
The mydriatic effect of this combination is returning to normal size in 2 days and reaches
independent of the effect of age or color of iris. pre-instillation size by the 10th day. Cycloplegia
Hydroxyamphetamine is useful in differe begins in about 15 minutes, reaches peak in about
ntiating preganglionic or central sympathetic 100 minutes and disappears in 7–12 days.
lesions from postganglionic lesions in Horner’s Atropine allows measurement of refractive
syndrome. In patients with preganglionic or error without interference by the accommodative
central lesion hydroxyamphetamine causes power of the eye and is, therefore, used for
pupillary dilatation by stimulating release of refraction in young children. However, shorter
norepinephrine from intact postganglionic fibers. acting cycloplegics are now preferred. People
This effect is not observed if the lesion involves above 40 years of age have decreased ability to
postganglionic fibers. accommodate and often refraction can be done
without cycloplegia. Ocular pain in patients with is discontinued. Treatment involves supportive
uveitis and corneal ulcer due to ciliary muscle measures such as maintaining the patent airways
spasm is relieved by atropine, which causes ciliary and symptomatic treatment such as for fever and
muscle relaxation. Some studies have shown that CNS excitation. Physostigmine is used as antidote
prolonged use of atropine may prevent or delay to quickly terminate the systemic toxicity of
the progression of myopia.19Atropine can also be atropine and is specially useful in patients with
used to provide pharmacological occlusion in the hallucinations, seizures and cardiac toxicity.
better eye for the treatment of amblyopia.20
Homatropine
Adverse Effects and Contraindications
Homatropine hydrobromide is a semi-synthetic
Topical instillation causes transient stinging. derivative of atropine. It is available commercially
Prolonged duration of mydriasis causes in a concentration of 2% and 5%. The mydriatic
photophobia and blurred vision for many days. effect appears in 10–20 minutes and reaches
In patients with narrow angle, atropine can peak in 30–40 minutes. Both the light and
precipitate an acute attack and is, therefore, accommodative reflexes are lost in 30 minutes.
contraindicated in patients with angle closure Pupil takes 1–3 days to recover to normal size. It
glaucoma. Topical atropine exacerbates aqueous is a less potent antimuscarinic agent than atropine
tear deficiency and is, therefore, contraindicated and thus produces significantly less cycloplegia
in patients with dry eyes. It is also contraindicated as compared to comparable doses of atropine
in patients with previous history of allergy. and cyclopentolate. The duration of cycloplegia
The pharmacological response to atropine produced by homatropine is longer than that
may be potentiated if administered to patients produced by cyclopentolate, especially in people
on drugs with antimuscarinic action such as with pigmented iris.21
antihistaminics, tricyclic antidepressants and Homatropine is primarily indicated for
monoamine oxidase inhibitors. therapeutic use in the treatment of anterior uveitis as
Atropine if absorbed systemically in significant its effects are similar to atropine. It is not a preferred
amount can cause drug for fundus examination or cycloplegic
Tachycardia, headache, flushing refraction because of its prolonged duration of
Dry mouth, heartburn action and relatively weak cycloplegic action.
Exacerbation of gut hypomotility, urinary The adverse effects and contraindications of
retention in patients with enlarged prostate homatropine are same as those of atropine.
CNS toxicity in elderly patients.
Atropine should be used with caution in pediatric Scopolamine (Hyoscine)

and elderly patients. It should be used in pregnant
The alkaloid scopolamine is obtained from the
and lactating mothers only if clearly indicated.
Measures should be taken to avoid excessive shrub Hyoscyamus niger and Scopolia carnfolica.
systemic absorption such as digital pressure for It is a non-selective antimuscarinic agent and has
2–3 minutes after topical administration. effects similar to atropine, although, the duration
Systemic atropine toxicity presents with dry of mydriatic and cycloplegic action is shorter.
and flushed skin, fever, blurred vision, rapid and The maximal mydriatic effect of scopolamine
irregular pulse, distended abdomen in infants, hydrobromide 0.5% solution appears in 20–30
mental aberrations and loss of neuromuscular minutes and pupil recovers to normal size in 1–3
coordination. Atropine poisoning is usually self- days. Cycloplegia appears in 30–60 minutes and
limiting and is rarely fatal if further administration persists for 3–7 days.22
Scopolamine even in low doses easily crosses recovery occurs in 12 hours. The light reflex
blood brain barrier and produces CNS effects such is also lost so the pupils do not constrict on
as drowsiness and confusions. A high incidence of exposure to bright light such as during binocular
idiosyncratic reactions with scopolamine has been indirect ophthalmoscopic examination or fundus
reported as compared to other anticholinergic photography. In patients who are sensitive to
drugs. Therefore, scopolamine is not a preferred atropine, cyclopentolate is used for the treatment
drug for fundoscopy, cycloplegic refraction or of anterior uveitis. However, if the inflammation
treatment of anterior uveitis. Its use is reserved is severe, more frequent instillation is required
for patients showing allergy to atropine. due to its short duration of action.
The adverse effects and contraindications
of scopolamine are same as those of atropine; Adverse Effects and Contraindications
however, CNS toxicity is more common.
Contraindications for scopolamine are same as The most common adverse effect of cyclopentolate
for atropine. is stinging, burning and tearing on initial
instillation. This effect is minimum at 0.5%
concentration but increases as the concentration
Cyclopentolate increases. In patients allergic to cyclopentolate,
Cyclopentolate is a water soluble ester and is ocular irritation, redness, facial rash, lacrimation,
available commercially in concentrations of 0.5, 1 white mucus discharge and blurred vision may
and 2% solutions. Instillation of two drops of 0.5% appear within minutes or hours. Repeated use of
solution 5 minutes apart or one drop of 1% solution high concentration solutions of cyclopentolate
causes mydriasis in 20–30 minutes and cycloplegia over prolonged period causes diffuse epithelial
in 30–40 minutes. Thus the onset of mydriasis punctuate keratitis with marked conjunctival
and cycloplegia requires almost the same time but hyperemia. Cyclopentolate can increase the
the time course of the two effects is not similar. intraocular pressure in patients with primary
Pupillary dilatation lags behind the cycloplegia. open-angle glaucoma and can precipitate an attack
Adequate cycloplegia appears even before the pupil of acute glaucoma in patients with narrow angle.
is fully dilated and refraction can be done early. Systemic absorption of cyclopentolate causes
It is a less effective mydriatic in blacks and adverse effects similar to atropine but the CNS
in people with black iris. In people with light effects are more common with cyclopentolate
iris, acceptable level of cycloplegia may appear as compared to atropine. CNS toxicity of
within 10 minutes of instillation of 1% solution. cyclopentolate is manifested as drowsiness,
In blacks and people with dark iris it may take up ataxia, disorientation, slurred speech, restlessness,
to 40 minutes for acceptable level of cycloplegia tactile and visual hallucinations. The CNS
to appear. The cycloplegic effect lasts longer in symptoms are particularly common in children
blacks and in people with black iris as compared when higher concentrations (2% or multiple
to people with light iris but in all eyes cycloplegia instillations of 1%) are used. CNS symptoms
terminates within 24 hours. usually subside within 2 hours in adults and 4–6
Cyclopentolate is the cycloplegic agent of hours in children without any permanent damage.
choice for routine cycloplegic refraction in A few cases of serious toxicity with epileptic
all age groups especially in infants and young seizures have been reported especially in children
children. The cycloplegia obtained is superior with neurological impairment.23,24 As the infants
to homatropine and parallels atropine. The onset and children especially those with neurological
of cycloplegia is faster and of shorter duration. impairment are more susceptible to adverse
Although complete recovery from cycloplegia effects of cyclopentolate, it should not be used
takes about 24 hours, an acceptable level of in concentrations higher than 0.5% in this group
of patients and systemic absorption should be used for fundus examination in neonates.
minimized by nasolacrimal occlusion. Hydroxyamphetamine 1% is combined with
Other peripheral adverse effects of anti tropicamide 0.25%. The size of the pupil after the
muscarinic agents due to systemic absorption use of combination is larger than that produced
such as flushed, dry skin and mucus membranes, by hydroxyamphetamine alone or tropicamide
fever and tachycardia are not observed with cyclo 0.5 and 1%.26 The combination has an equivalent
pentolate. Treatment of cyclopentolate toxicity is mydriatic efficacy and greater cycloplegic efficacy
the same as that of atropine toxicity. as compared to phenylephrine 2.5% followed by
tropicamide 0.5% instilled separately for the first
Tropicamide 45–60 minutes.27 The mydriasis produced with
the combination is sufficient to allow indirect
Tropicamide is a synthetic derivative of tropic
ophthalmoscopy and fundus photography and
acid. It is a non-selective antimuscarinic agent. Its
does not vary with age or iris pigmentation. The
penetration through corneal epithelium is better
combination is also more comfortable to use as
than atropine, homatropine and cyclopentolate
and, therefore, it causes quick onset of mydriasis, compared to phenylephrine 2.5% or tropicamide
which lasts for a short duration. It is available 0.5%.
in two concentrations, 0.5 and 1%. Maximum A combination of tropicamide 0.5% and
mydriasis occurs in 20–40 minutes and pupil phenylephrine 0.5%, injected intracamerally
reaches pre-instillation size in 6 hours. Mydriatic has been shown to be safe and effective in
effect of tropicamide is not dependent on dilating pupils in cases with poor mydriasis
concentration and 1% concentration produces after preoperative instillation.28 Combination of
only slightly larger pupil. Cycloplegia appears tropicamide 1% and phenylephrine 2.5% has
in 30–35 minutes and is dose-related. The shown significantly greater efficacy as mydriatic
mydriatic effect of tropicamide is stronger than in dark eyes subjects as compared to tropicamide
its cycloplegic effect. The lower concentration is 1% and cyclopentolate 1% combination.29
used for mydriatic effect and higher concentration
for cycloplegia. It is not a drug of choice for Adverse Effects and Contraindications
cycloplegic refraction but 1% concentration has Adverse effects include stinging and burning
been found to be useful for measuring distance sensation especially after instillation of 1%
refractive error in school children with mild to solution. In patients with narrow angle,
moderate hyperopia. intraocular pressure may rise. It is, therefore,
Tropicaimde is free form vasopressor effects contraindicated in patients with angle-closure
and is the safest mydriatic to use in neonates and glaucoma. Tropicamide is significantly absorbed
patients with hypertension or other cardiovascular in systemic circulation but it has poor affinity for
disease. Tropicamide 1% was also reported systemic muscarinic receptors and, therefore, its
to cause greater mydriasis as compared to systemic adverse effects are rare. Hypersensitivity
phenylephrine 2.5% and a combination of to tropicamide has been reported.30 Patients with
tropicamide 1% and phenylephrine 2.5% was hypersensitivity to belladonna also show cross-
more effective than either of them used alone.25 sensitivity to topical tropicamide.
Tr o p i c a m i d e a n d c y c l o p e n t o l a t e a r e
often combined with phenylephrine and
hydroxyamphetamine to overcome the constrictor REFERENCES
effect of cholinergic stimulation, particularly 1. Cogan DG. Accommodation and the auto
on exposure to bright light. Phenylephrine nomic nervous system. Arch Ophthalmol.
1% combined with cyclopentolate 0.2% is 1937;18(5):739–66.
2. Stephens KG. Effect of the sympathetic nervous in patients with sympathetic denervation. Am J
system on accommodation. Am J Optom Physiol Ophthalmol. 1978;85(6):862–8.
Opt. 1985;62(6):402–6. 15. Robertson D. Contraindication to the use of
3. Gil DW, Krauss HA, Bogardus AM, WoldeMussie ocular phenylephrine in idiopathic orthostatic
E. Muscarinic receptor subtypes in human iris- hypotension. Am J Ophthalmol. 1979;87(6):819–
ciliary body measured by immunoprecipitation. 22.
Invest Ophthalmol Vis Sci. 1997;38(7):1434– 16. Abbott WO, Henry CM. Paredrine (β-4-
42. hydroxyphenylisopro-pylamine): a clinical
4. Heath P, Geiter CW. Use of phenylephrine hydro investigation of a sympathomimetic drug. Am J
chloride (Neosynephrine) in ophthalmology. Med Sci. 1937;193:661–73.
Arch Ophthalmol. 1949;41(2):172–7. 17. Semes LP, Bartlett JD. Mydriatic effectiveness
5. Munden PM, Kardon RH, Denison CE, Carter of hydroxyamphetamine. J Am Optom Assoc.
KD. Palpebral fissure responses to topical 1982;53(11):899-904.
adrenergic drugs. Am J Ophthalmol. 1991; 18. Gartener S, Billet E. Mydriatic glaucoma. Am J
111(6):706–10. Ophthalmol. 1957;43(6):975–6.
6. Chiri NB, Gold AA, Breinin G. Iris cysts and 19. Brodstein RS, Brodstein DE, Olson RJ, Hunt
miotics. Arch Ophthalmol. 1964;71:611–6. SC, Williams RR. The treatment of myopia with
7. Thompson HS, Menscher JH. Adrenergic atropine and bifocals. A log-term prospective
mydriasis in Horner’s syndrome; hydrox study. Ophthalmology. 1984;91(11):1373–8.
yamphetamine test for diagnosis of postganglionic 20. Simons K, Stein L, Sener EC, Vitale S,
defects. Am J Ophthalmol. 1971;72(2):472–80. Guyton DL. Full-time atropine, intermittent
8. Fraunfelder FT, Meyer SM (eds). Drug-induced atropine, and optical penalization and binocular
ocular side effects and drug interactions. outcome in treatment of strabismic amblyopia.
Philedelphia: Lea and Febiger, 1989; Chapter 6. Ophthalmology. 1997;104(12):2141–55.
9. Alpay A, Ermis B, Ugurbas SC, Battal F, Sagdik 21. Emiru VP. Response to mydriatics in the African.
HM. The local vasoconstriction of infant’s skin Br J Ophthalmol. 1971;55(8):538–43.
following instillation of mydriatic eye drops. Eur 22. Marron J. Cycloplegia and mydriasis by use
J Clin Pharmacol. 2010;66(11):1161–4. of atropine, scopolamine and homatropine-
10. Raison-Peyron N, Du Thanh A, Demoly P, Guillot paredrine. Arch Ophthalmol. 1940;23(2):
B. Long-lasting allergic contact blepharocon- 340–50.
junctivitis to phenylephrine eyedrops. Allergy. 23. Kennerdell JS, Wucher FP. Cyclopentolate
2009;64(4):657–8. associated with two cases of grand mal seizure.
11. Martin-Flores M, Mercure-McKenzie TM, Arch Ophthalmol. 1972;87(6):634–5.
Campoy L, Erb HN, Ludders JW, Gleed RD. 24. Fitzgerald DA, Hanson RM, West C, Martin F,
Controlled retrospective study of the effects of Brown J, Kilham HA. Seizures associated with
eyedrops containing phenylephrine hydrochloride 1% cyclopentolate eyedrops. J Paediatr Child
and scopolamine hydrobromide on mean arterial Health. 1990;26(2):106–7.
blood pressure in anesthetized dogs. Am J Vet 25. Park JH, Lee YC, Lee SY. The comparison
Res. 2010;71(12):1407–12. of mydriatic effect between two drugs of
12. Fraunfelder FT, Scafidi AF. Possible adverse different mechanism. Korean J Ophthalmol.
effects from topical ocular 10% phenylephrine. 2009;23(1):40–2.
Am J Ophthalmol. 1978;85(4):447–53. 26. Cooper J, Feldman JM, Jaanus SD, et al.
13. Calenda E, Richez F, Muraine M. Acute Pupillary dilation and fundoscopy with 1.0%
hypertension due to phenylephrine eyedrops in hydroxyamphetamine plus 0.5% tropicamide
a newborn. Can J Ophthalmol. 2007; 42(3):486. (Paremyd) versus tropicamide (0.5% or 1%) as
14. Kim JM, Stevenson CE, Mathewson HS. a function of iris and skin pigmentation and age.
Hypertensive reaction to phenylephrine eye drops J Am Optom Assoc. 1996;67(11):669–75.
27. Zeise MM, McDougall BWJ, Bartlett JD vivo efficacy and in vitro safety studies. Clin
et al. Comparison of efficacy and tolerance Experiment Ophthalmol. 2011;39(5):456–61.
between 1.0% hydroxyamphetamine plus 0.5% 29. Anderson HA, Bertrand KC, Manny RE,
tropicamide (Paremyd) and 0.5% tropicamide Hu YS, Fern KD. Comparison of two drug
combined with 2.5% phenylephrine. J Am Optom
combinations for dilating dark irides. Optom Vis
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28. Mori Y, Miyai T, Kagaya F, Nagai N, Osakabe
Y, Miyata K, et al. Intraoperative mydriasis by 30. Wahl JW. Systemic reaction to tropicamide. Arch
intracameral injection of mydriatic eye drops: in Ophthalmol. 1969;82(3):320–1.
ChapteR 7
Ophthalmic Dyes
OVERVIEW Thus, the maximum fluorescence is achieved at

physiological pH and increase beyond 8 reduces
Dyes as a diagnostic tool are widely used in the fluorescence. The wavelength of absorbed
ophthalmic practice. Fluorescein, synthesized light also affects the intensity of fluorescence
by Baeyer in 1871, was the first dye used for and a maximum intensity is produced at the
diagnostic purpose. 1,2 Several such dyes are wavelength of 530-nm.3,4
currently in use for various diagnostic purposes Fluorescein is available for topical use as
such as to assess the integrity of corneal surface, solution and in the form of fluorescein-impregnated
patency of lacrimal system, anterior segment filter paper strips. Fluorescein solution is
and retinal vascular functions and Goldmann highly susceptible to bacterial contamination
tonometry. and especially by Pseudomonas aeruginosa.5
To prevent the bacterial contamination of
Fluorescein Sodium solutions, preservatives such as chlorobutanol
and thimerosal have been used. Non-preserved
Fluorescein is a dye of xanthine series with a preparations are used in sterile single-dose vials.
molecular weight of 376 kd and solubility of Wet filter paper strips when applied to eye release
50% in water at 15°C. It is an acidic dye and dye and are used clinically for various diagnostic
is formulated as sodium salt. When exposed to purposes. Use of filter paper strips helps to avoid
light, fluorescein absorbs certain wavelength the risk of bacterial contamination.
and then emits light at longer wavelength. The
wavelength of emitted light can be measured
Clinical Uses
spectrophotofluorimetrically. Fluorescein does not
stain tissues but shows characteristic green color Topical: Fluorescein is widely used topically for
due to its fluorescent properties. The fluorescence a variety of diagnostic and other purposes:
of fluorescein in solution is affected by several 1. Assessment of ocular surface integrity:
factors. An increase in the concentration increases Application of dye in the cul-de-sac allows
the intensity of fluorescence and a maximum detection of corneal and conjunctival lesions
fluorescence is achieved at 0.001% concentration. such as abrasion, ulcer, edema and presence
The intensity of fluorescence is also affected by of a foreign body. At physiological pH, dye
pH. As the fluorescein is an acidic dye, at pH less is highly ionized and fails to penetrate intact
than 2, its cationic form predominates, which corneal epithelium. However, if the corneal
gives a blue-fluorescence. At physiological pH epithelium is not intact dye comes in contact
of 7, the anionic form predominates, which with stroma and when observed with cobalt-
gives a brilliant yellow-green fluorescence. blue filter of slit lamp, the epithelial defect
Ophthalmic Dyes 97
appears as green fluorescent spot. The reason 5. Contact lens fitting: Staining of tear film
for this color change from orange-yellow with fluorescein helps in determining the
to green is not fully understood. According fitting of rigid gas permeable contact lenses
to some, penetration of dye into the stroma as the areas where the lens makes contact
allows it to come in contact with interstitial with cornea, minimal or no fluorescence is
fluid derived from aqueous humor leading observed. Besides aiding in contact lens fitting,
to pH-dependent change in the color of the fluorescein staining also helps in assessing
dye. According to other views, the dye enters the integrity of corneal surface in contact lens
the dead cells and staining appears due to the wearers.
fluorescence of intracellular structures.3,6 6. Assessment of the patency of lacrimal
2. Assessment of tear film stability: Tear break- system: Fluorescein can be used to assess
up time (TBUT), which is measured as the patency of the lacrimal system. The dye is
time interval between the last complete instilled into the lower fornix. Following
blink and appearance of the first dry spot instillation, appearance of dye in nose or
in the tear film, is commonly used to assess posterior pharynx, is an indicator of the
the dry eyes and efficacy of tear substitutes. patency of lacrimal apparatus.
The test requires application of dye to bulbar Intravenous: Fluorescein is used by intravenous
conjunctiva followed by observation with route to study vascular integrity and abnormalities
slit lamp until the dry spot appears in the tear in posterior and anterior chambers.
film. TBUT of less than 10 seconds indicates 1. Fluorescein angiography: Intravenous
tear film instability. A wide variation in TBUT injection of 10 mL of fluorescein (5%) makes
have been reported and, therefore, the validity the dye appear in central retinal vein in
of this test is questionable. 10–15 seconds.9 Fluorescein binds to plasma
3. Applanation tonometry: Fluorescein (0.25%) albumin and this protein binding prevents
is used for measurement of intraocular pressure it from passing through the blood-ocular
using Goldmann applanation tonometer. Dye barrier. In the bloodstream, fluorescein is
stains the meniscus of tear fluid around the excited by a wavelength of 465 nm and
flattened corneal surface and allows clear emits a wavelength of 525 nm. Retinal
visualization of the apex of the wedge- blood vessels are visualized in high contrast.
shaped meniscus. An anesthetic solution is Nonvascularized areas are seen as dark areas
first instilled and sufficient time is allowed against green fluorescing background whereas
for the anesthetic to get absorbed before the neovascularization produces enhanced
dye is applied. Instillation of dye together fluorescence. Pathological lesions causing
with anesthetic agent reduces fluorescence as enhanced capillary permeability are visualized
the acidic pH of anesthetic solution ionizes as leakage of the dye in extravascular
fluorescein, which now has poor fluorescence. space. Some retinal abnormalities allow
Although Goldmann applanation tonometry greater visibility of choroidal fluorescence.
can be performed without using fluorescein, Fluorescein angiography is, therefore, very
the IOP measurements are significantly useful in the diagnosis of a wide range of
lower.7,8 conditions like diabetic retinopathy, central
4. Detection of aqueous leakage: Fluorescein serous choroidopathy, papilledema, disciform
is used to detect leakage of aqueous humor macular degeneration, choroidal hemangiomas
such as during corneal transplant or from the and melanomas.
surgical wounds. In cases of leakage, the dye 2. Iris angiography: Fluorescein after injection
stains the leaking aqueous, which appears as into the antecubital vein, appears in the radial
a bright green streak flowing over the cornea.6 vessels of iris in 9–20 seconds. Iris vessels
are better visualized in people with blue iris from all patients as intravenous fluorescein can
as compared to brown iris as the pigment also cause allergic reactions such as urticaria.
distribution affects the visualization of iris Serious allergic reactions like anaphylaxis are
vessels. Pathological conditions of iris such rare. Intravenous fluorescein colors the urine
as tumor or infarct can be visualized in iris and skin temporarily and appears in milk 76
angiogram. hours after intravenous injection. 14 Other
3. The rate of aqueous flow can be determined by adverse effects include pain at the injection site,
measuring the time course of the changes in paraesthesias of tongue and lips, dizziness, and
fluorescein concentration in anterior chamber rarely fainting.
with the help of a slit lamp fluorophotometer.
4. Vitreous fluorophotometry helps in detecting Fluorexon
presence of dye in the vitreous. Normally the
blood-retinal barrier does not allow dye to Fluorexon is N,N-bis(carboxymethyl)-amino
pass through and appear in the vitreous and, ethylfluorescein tetrasodium salt. Its molecular
therefore, appearance of dye in vitreous is an weight is 710 kd and it has a pale yellow-brown
indicator of the damage to blood-retinal barrier. color. It stains the epithelial defects and the
devitalized tissue. Observation of fluorescence
Oral: Fluorescein can be administered orally
requires enhancement by yellow filter.
to study certain lesions in retina. For adults 1
or 2 gram powder or 3 vials of 10% fluorescein
mixed in a citrus drink are used. For children Clinical Uses
1mL of 10% fluorescein per 20 mL of fruit juice Fluorexon is used as an aid in contact lens fitting
per 5 kg body weight is used.10 Following oral as it is less readily absorbed by the soft lens
administration, dye appears in the fundus in about material. The use of this dye, therefore, allows
15 minutes and maximum fluorescence appears visualization of tear film under the lens. Fluorexon
in 45–60 minutes.11 The adverse effects are less is a useful aid in fitting hybrid lenses and fitting
likely after oral administration as compared to of lenses in cases like keratoconus where rigid
intravenous administration. lens is placed over a hydrogel lens. Fluorexon is
not a widely used dye in clinical practice as the
Adverse Effects evaluation of contact lens fitting is as effective
in the presence as in the absence of the tear film
Topical fluorescein may cause transient ocular visualization.
irritation. Topical fluorescein stains the soft
contact lenses and, therefore, soft lenses should
Adverse Effects
be reinserted after 1–2 hours or following
thorough rinsing of upper and lower fornix with Fluorexon is remarkably non-toxic to ocular
sterile saline or extraocular irrigating solutions. tissue. Topical application can cause stinging
Intravenous injection of 10% fluorescein causes sensation and conjunctival injection. If allowed
nausea in 10% of the patients with higher to remain in contact with soft contact lenses,
incidence among females. Incidence of nausea lenses can get stained. Repeated rinsing with
increases with increasing concentrations of saline helps to remove the dye from the lenses.
fluorescein.12 Slow intravenous injection also Fluorexon is not recommended for use with
reduces the incidence of nausea.13 Promethazine high water content (60% or higher) lenses. Such
50 mg orally can be used one hour before lenses can absorb significant quantity of dye and
intravenous fluorescein to reduce the incidence will be discolored. Fluorexon solution allows
of nausea in susceptible patients. Family and easy bacterial contamination and is, therefore,
personal history of allergy must be obtained dispensed in single-dose sterile pipettes.
Ophthalmic Dyes 99
Rose Bengal with rose bengal staining. This dye is particularly

useful in identifying herpetic corneal ulcer as it
Rose bengal is 4,5,6,7-tetra-chloro-21,41,51,71- gives characteristic staining to dendritic margins.
tetraiodo derivative of fluorescein, which gives However, because of its antiviral properties,
the stained tissue a pink or magenta color when subsequently performed culture test may provide
viewed with white light. Although known as a a false negative result leading to inappropriate
vital dye that colors the dead, degenerated tissue treatment.
and mucus strands, recent studies have shown Intravenous: In animal studies, intravenous
that rose bengal also stains healthy cultured injection of rose bengal has been shown to
cells.15,16 The nucleus of healthy cells has been cause vascular occlusion by photothrombosis.
shown to retain the dye. Rose bengal has also been It photochemically induces endothelial damage
shown to possess cytotoxic properties especially leading to platelet aggregation and vascular
upon exposure to light. 15,17 Rose bengal is a occlusion.21,22 Since the thrombus can not be
photoreactive compound and in the presence of degraded by tissue plasminogen as it mainly
55-nm wavelength and oxygen it generates singlet consists of platelets and no fibrin, it is long
oxygen.18,19 Singlet oxygen is highly reactive and lasting. The method has been used in rabbits to
damages cell proteins and DNA. Because of this cause occlusion of corneal neovascularization.
action, rose bengal is effective against a wide Animal studies done so far indicate potential use
range of micro-organisms like bacteria, viruses of rose bengal in the treatment of ocular surface
and protozoa. In vitro studies have shown that disorders with overgrowth such as chemical
rose bengal due to its intrinsic toxicity damages burns, contact lens-induced vascularization,
unprotected epithelial cells. However, in the exudative keratopathy and vascularized cornea.23
presence of albumin and mucus such toxicity
does not occur. This indicates that the rose bengal
Adverse Effects
staining of epithelial cells is not due to staining
of dead cells but due to absence of protective tear Topical application of rose bengal causes
film as is seen in keratoconjunctivitis sicca. stinging and smarting. Rose bengal stains skin,
clothing and contact lenses. Intravenously
Clinical Uses administered rose bengal is non-toxic to human.
The dye is metabolized in liver and, therefore, is
Topical: For topical use rose bengal is used as 1% contraindicated in patients with impaired liver
solution or in the form of sterile impregnated filter function.
paper strips. Its most frequent clinical use is in the
evaluation of dry eye syndromes. The efficacy
of rose bengal used alone in the differential Lissamine Green
diagnosis of dry eye is debatable. It has been Lissamine green is a vital stain and just like rose
recommended that rose bengal staining must be bengal stains mucus and dead degenerated cells.
combined with other tests such as fluorescein stain It gives a bluish-green color to the stained tissue
or tear function tests for better efficacy. A grading and its staining effect is longer lasting than rose
system to quantify rose bengal staining described bengal. It has a molecular weight of 576.6 kd and
by George et al. can be used to assess the severity is also used as food colorant.
of dry eye.20 Rose bengal staining has also been
used to assess the treatment efficacy, however, its
Clinical Uses
utility remains debatable. The evaluation of most
types of conjunctival and corneal lesions such as Lissamine green 1% as solution or filter paper
abrasions, ulcers, foreign bodies, conjunctival strip is used for assessing dry eye conditions,
dysplasia and metaplasia has also been done recurrent corneal erosions and herpetic ulcers. Its
staining effect is easier to see in red and inflamed the success of this treatment depends on
eye and that is why it is especially useful when identification and accurate localization of the
a red dye is not desirable or in combination with areas of neovascularization. ICG angiography
a red dye. has been shown to provide better localization
and identification of these areas as compared
Adverse Effects to fluorescein. The dye stays in the areas of
neovascularization long after it disappears
Lissamine green does not cause any ocular from surrounding areas. Therefore, ICG is of
irritation on topical application. No other adverse particular value in visualizing poorly defined
effects are known. The dye, however, stains the membranes overlying hemorrhage or lying
soft lenses and should not be used in eyes with close to previously treated areas. Use of infrared
lenses in place. scanning laser ophthalmoscope further enhances
the resolution in ICG videoangiography.
Indocyanine Green
Indocyanine (ICG) is a water soluble Adverse Effects
tricarbocyanine dye. When injected intravenously, Intravenous use of ICG is generally safe without
it is highly protein bound. Extensive protein many adverse effects. It does not stain skin,
binding does not allow dye to leak from the mucous membranes or urine. Use of ICG is,
capillaries and, therefore, the details of choroidal however, associated with allergic reactions. ICG
and retinal vasculature can be studied. ICG is contains small amount of sodium iodide and
dissolved in aqueous solvent at a concentration of should not be used in patients with allergy to
12.5 mg/mL and a total dose of 50 mg is injected in iodine or shellfish.
anticubital vein at a rate of 1 mL/sec.24 Following
intravenous injection, photographs are taken at 1–2
Methylene Blue
second interval until full fluorescence is achieved.
Subsequently, photographs are taken at increasing Methylene blue is an aniline dye and just like
interval over 30–40 minutes until fluorescence rose bengal stains dead devitalized cells and
disappears. ICG is taken up exclusively by liver mucus. It is used as 5% solution and also has
and is a helpful index of liver functions. bacteriostatic properties.
Clinical Use Clinical Uses

It is used as fluorescent dye for retinal and Methylene blue is mainly used to stain lacrimal
choroidal angiography. It shows peak absorption sac before dacryocystorhinostomy. Before surgery
at 805 nm and maximum emission at 835 nm. the sac is irrigated with dye. The dye is allowed to
This near infrared range, provides better viewing remain in sac for several minutes and is washed
of angiograms in the presence of media opacities out of the sac before starting surgery. Methylene
and subretinal exudation. Choroidal vasculature blue is also used to visualize anterior lens capsule
is better visualized with ICG than fluorescein. during cataract surgery and in gonioscopic ab
Rapid choroidal filling is also better visualized interno laser sclerostomy. It can be used topically
with ICG. Videoangiography using ICG is a to stain corneal nerves.
useful tool in studying a variety of choroidal
pathologies such as congenital, ischemic,
Adverse Effects
inflammatory or degenerative. ICG angiography
is commonly used to characterize choroidal Topical application of methylene blue causes
neovascularization. Choroidal neovascularization ocular tissue irritation. It is also contraindicated
is treated with laser photocoagulation and for use in patients who are allergic to the dye.
Ophthalmic Dyes 101
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1979;97(12):2331–2. neovascularization by intravenous rose bengal
12. Willerson D, Tate GW, Baldwin HA, Hernsberger and argon laser irradiation. Arch Ophthalmol.
PL. Clinical evaluation of fluorescein 25%. Ann 1988;106(5):680–5.
Ophthalmol. 1976;8(7):833–42. 24. Yannuzzi LA, Slakter JS, Sorenson JA, Guyer
13. Charzan BI, Balodimos ML, Konez L. Untowards DR, Orlock DA. Digital indocyanine green vide-
effects of fluorescein angiography in diabetic oangiography and choroidal neovascularization.
patients. Ann Ophthalmol. 1971;3(1):42–9. Retina. 1992;12(3):191–223.
ChapteR 8
Antibacterial Agents
OVERVIEW idea of ‘selective toxicity’, which has remained

not only a relevant feature but pertinent one.
Anti-infective agents are drugs used to treat In 1877, Louis Pasteur showed that soil
infections. A more common term, which carries bacteria could render Bacillus anthracis harmless
a similar connotation and is used widely but and at about the same time, Rudolf Emmerich
not accurately is the “antibiotics”. The term showed that Vibrio cholera could not survive
“antibiotic” is used loosely to refer to drugs, in the presence of streptococci. Following
natural or synthetic, used to treat bacterial this, German scientist E. de Freudenreich
infections. The term “antibiotic” was coined by demonstrated that an isolated product from
Selman Waksman, a professor of biochemistry bacterium had antibacterial properties. In the early
and microbiology, who discovered numerous 1920s, the British scientist Alexander Fleming
antibiotics, the first of which was streptomycin. reported that human tears contained lysozyme that
He referred antibiotics as substances produced by could lyse bacterial cells. It was the first example
microorganisms, which were able to either kill or of an antibacterial agent found in humans but
inhibit the growth of other microbes. As such, the was devoid of selective toxicity. Later, Fleming
original definition excludes synthetic compounds. discovered a connection between a fungus and a
A more precise term and closer to anti-infectives substance that had antibacterial properties, thus
is antimicrobial drugs, which refers to drugs, natural the antibiotic properties of penicillium were
or synthetic, for the treatment of infections caused reported. This discovery changed the course of
by microorganisms, not limited to bacteria but also medicine.
the fungi and protozoa. In practice, however, the
term “antibiotics” is used interchangeably with Classification
“antimicrobials” or “anti-infectives”.
There are several ways to classify antibiotics.
Schemes for classification may be based on their
Historical Perspectives
origin (natural or synthetic), route of administration
In the 1800, with acceptance of a theory, which (injectable, oral, topical), antibacterial activity
linked microorganisms as etiological agents with (bacteriostatic or bactericidal), spectrum of
variety of ailments, scientists began work on activity (broad and narrow spectrum) or the
searching for compounds, which antagonised the chemical structure, which is the most useful
survival of disease-causing microbes in humans. pharmacological classification. Antibiotics within
The aim was to find a compound that would be a structural class will generally have similar
toxic to the microbes but not to humans who were patterns of effectiveness, toxicity, and allergic
infected by such microbes, hence, developed the potential.
Antibacterial Agents 103
The commonly used types of antibiotics are Alexander Fleming in 1928. The first successful
penicillins, fluoroquinolones, cephalosporins, clinical use of penicillin was in 1930 when Cecil
macrolides, and tetracyclines. While each class George Paine attempted to use penicillin in the
consists of several drugs, each drug has its own treatment of neonatal gonococcal infection,
distinctive features. however, the wide clinical use of penicillin started
only in 1941.1
BETA LACTAM ANTIBIOTICS The beta lactam antibiotics are grouped
together based upon a shared structural feature, a
Beta lactam antibiotics are among the most thiozolidine ring and a beta lactam ring (Fig 8.1)
commonly prescribed drugs. The first beta lactam connected to a side chain. Their structures are
antibiotic, penicillin, was discovered by Sir shown in Figure 8.2.
Figure 8.1 Penicillin structure; (a) The characteristic

beta lactam ring; (b) Thiozolidine ring
Figure 8.2 Chemical structure of the beta lactam family

Majority of the beta lactam antibiotics The walls of bacteria are made of a complex
are semi-synthetic derivatives of the natural material called peptidoglycan containing both
comp ounds with modifications of the 6 (7) amino acids and amino sugars. The two types of
beta-acylamido side chains of penicillins and amino sugars it contains are N-acetylglucosamine
cephalosporins (Fig. 8.3). (NAG) and N-acetylmuramic acid (NAM). So,
Synthetic beta lactam antibiotic are also essentially peptidoglycan is a linear polymer
available (Fig. 8.4). The beta lactam chain is of NAG alternating with NAM linked by a
essential for biological activity, whereas the side glycosidic bond. A four or five amino acids
chains are primarily responsible for determining peptide chain is attached to each NAM and these
the antibacterial spectrum. Modification of these chains form covalent bonds with amino acids in
adjacent chains. The bonds may be direct to the
side chains has a profound influence on their
next chain or include additional peptide cross
antibacterial activity.
bridges such as the pentaglycine bridge, which
Due to the similarity in their chemical structure,
extend to chains in the same plane as well as to
all beta lactam antibiotics are characterized by the chains above and below (Fig. 8.5). This results
same properties such as the same mechanism in linear strands of peptidoglycan cross-linked
of antibacterial action, same modes of bacterial into a fishnet-like polymer that surrounds the
resistance and presence of allergic cross-reaction.2 bacterial cell and confers osmotic stability in the
hypertonic milieu of the infected patient. Gram-
Mechanism of Action positive bacteria have thicker peptidoglycan
layer than Gram-negative, however, the later
The cell walls play a crucial role in the bacterial contains an additional phospholipid layer in the
cell protection especially from internal turgor cell membrane. The particles larger than 2 nm
pressure caused by the much higher concentrations cannot pass freely through the peptidoglycan
of proteins and other molecules inside the cell meshwork of the cell wall of both the Gram-
compared to its external environment. Loss or positive and Gram-negative bacteria.3 Synthesis
damage of this integral protective layer results in of the bacterial cell wall peptidoglycan consists of
bacterial cell death. three stages involving about 30 different enzymes.
Figure 8.3 Semi-synthetic beta lactam antibiotics

Figure 8.4 Synthetic beta lactam antibiotics
Figure 8.5 Peptidoglycan layer and the site of action of beta lactam antibiotics
During the first stage, the peptidoglycan can be inhibited by antibiotics such as vancomycin
monomers are synthesized in the cytoplasm. The and bacitracin. The third stage involves the
first stage can be inhibited by fosfomycin and formation of cross linkages between peptidoglycan
cycloserine. The second stage, which occurs in layers and the attachment of nascent peptidoglycan
the cell membrane, is the construction of a linear to the cell wall. The enzyme essential for these cross
polymer of a peptidoglycan chain. The second stage linkages is the D-alanyl-D-alanine-transpeptidase
also known as “penicillin-binding protein” (PBP).4 PENICILLINS (Table 8.1)
Beta lactam antibiotics have the structural similarity
to D-alanyl-D-alanine that leads to their irreversible Antibacterial Activity
binding to the active site of PBP and causes PBP
inhibition. Irreversible inhibition of PBP prevents Natural Penicillins
the final crosslinking of the nascent peptidoglycan
The natural penicillins are narrow spectrum
layer. Inhibition of cross-linkage by beta lactams
antibiotics primarily effective against Gram-
causes a weakening of the bacterial cell wall.
positive and a few Gram-negative bacteria. The
Defective walls fail to protect the bacteria from
spectrum of antibacterial activity of penicillin
bursting in hypotonic surroundings, which causes
includes:
disruption of bacterial cells (bactericidal effect). Gram-positive cocci (Staphylococcus species
Therefore, beta lactam antibiotics have little effect
and Streptococcus species)
on resting bacteria but are lethal to dividing bacteria. Gram-negative cocci (Neisseria gonorrhoeae,
Neisseria meningitidis)
Mechanism of Bacterial Resistance Gram-positive bacilli (Bacillus anthracis,
All beta lactam antibiotics have the same modes Corynebacterium diphtheriae, Clostridium
of the development of bacterial resistance. There tetani and others)
are three important modes by which bacteria Listeria species
acquire resistance against beta lactam antibiotics: Spirochetes (Treponema pallidum, Leptospira
production of inactivating enzymes, altered target species)

and altered permeability. Majority of Gram-negative bacilli are
The first mechanism is associated with insensitive to natural penicillins. The antibacterial
enzymatic hydrolysis of the beta lactam ring activity of natural penicillins is considerably
by the bacterial enzymes, beta lactamases or limited by the secondary bacterial resistance.
penicillinases. The beta lactamase family includes Currently, most strains of S. aureus and N. gonor
more than 300 different enzymes, that are rhoeae are resistant to penicillin.7,8
classified according to their hydrolytic spectrum, Penicillin G is highly acid-labile and is
susceptibility to inhibitors, genetic localization hydrolyzed in the presence of gastric acid.
(plasmidic or chromosomal), gene or amino acid Therefore, penicillin G is administered parente
protein sequence.5,6 This mechanism of beta lactam rally. Penicillin V can be given orally as it is more
resistance is very common in Gram-negative resistant to hydrolysis by acidic gastric secretions
bacteria such as E. coli, Klebsiella species, Proteus and is absorbed to a greater extent than penicillin
species, Pseudomonas aeruginosa. G. Procaine and benzathine penicillins are so
Resistance to methicillin and other penicil called depot penicillins because they provide a
linase resistant penicillins is associated with tissue depot from which absorption takes place
alteration of PBP structure. Such altered PBP over several hours to several days. They should
does not allow for the binding to all beta lactams, be given by deep intramuscular injections.
including cephalosporins and carbapenems. This Benzathine penicillin has longer action than
mode of penicillin resistance is often manifested procain penicillin.9
in Staphylococcus aureus and such strains are Penicillins penetrate well into all parts of the
labeled as methicillin-resistant Staphylococcus ocular tissue such as the lid margins, conjunctival
aureus (MRSA). sacs, corneae and lacrimal sacs but not the
Lastly, another mechanism of resistance to ocular muscles. Penicillins cross the placenta
beta lactam, decreased permeability through cell and are also distributed into breast milk. They
wall and membrane proteins, is more common are not metabolized and are excreted unchanged
among Gram-negative bactreria. through the kidneys by filtration and active
Table 8.1 Classification of penicillins
A. Natural Penicillins i. Short-acting Penicillin G (benzylpenicillin)

Penicillin V (Phenoxymethylpenicillin)
ii. Long-acting Procaine penicillin
Benzathine penicillin
B. Semi-synthetic i. Aminopenicillins Ampicillin
Penicillins Amoxicillin
Bacampicillin
ii. P
enicillinase resistant Methicillin
Penicillins (antistaphylococcal Oxacillin
Penicillins) Cloxacillin
Dicloxacillin
Nafcillin
iii. Extended-spectrum Ureidopenicillins
penicillins (Antipseudomonal Azlocillin
penicillins) Mezlocillin
Piperacillin
Carboxypenicillins
Carbenicillin
Carbenicillin indanyl sodium
Ticarcillin Piperacillin
iv. Penicillins and beta lactamase Ampicillin/sulbactam
inhibitor combinations Amoxicillin/clavulanate
Piperacillin/tazobactam
Ticarcillin/clavulanate
tubular secretion. Renal excretion is rapid but These acid-stable penicillins are given orally
concurrent administration with probenecid can and are reasonably well absorbed. However, food
slow the excretion rate. The plasma half-life is interferes with their absorption and they have to
about 30 minutes, but in premature neonates be taken at least an hour after meals. They can
and individuals with impaired kidney function, also be administered intravenously. Excretion for
excretion is considerably delayed, requiring all is via kidneys, with the exception of nafcillin,
longer dosing intervals and dose reduction.10 which undergoes biliary excretion.
Penicillinase-resistant Penicillins Aminopenicillins

Penicillinase resistant penicillins include In general, this class retains the spectrum of
methicillin, nafcillin, oxacillin, cloxacillin activity of penicillin G or the natural penicillins.
and dicloxacillin. Drugs in this group are They differ from the natural penicillins in that
structurally resistant to beta lactamase activity. they have enhanced ability to penetrate Gram-
They have a narrower spectrum of activity than negative organisms thus they have greater activity
the natural penicillins. This class is indicated for against
infection by beta lactamase producing strains Enterobacteriaceae (E. coli, Shigella species,
of Staphylococcal species including S. aureus. Salmonella spp., Proteus mirabilis)

Methicillin-resistant strains of Staphylococci are Haemophilus influenzae
resistant. Helicobacter pylori

Aminopenicillins are not active against penicillins to include beta lactamase-producing
Klebsiella species, Enterobacter species, Pseudo strains of S.aureus and some Gram-negative
monas aeruginosa, Citrobacter, Serratia, indole- bacteria. The combination of clavulanic acid
positive Proteus species, and other Gram-negative and ticarcillin is known as timentin. It is given
aerobes that are commonly encountered in parenterally. The combination increases the
hospital-acquired infections. spectrum of activity of ticarcillin to include Gram-
Like the natural penicillins, they are susce negative aerobic organisms, Staphylococcus
ptible to hydrolysis by beta lactamase. They aureus and Bacteroides. Clavulanic acid is also
have a similar pharmacokinetic profile as natural combined with amoxicillin, and the combination
penicillins. They are administered orally and, is known as augmentin. Augmentin is given orally
amoxicillin has better absorption compared to and effectively treats infection by beta lactamase
ampicillin and bacampicillin. Ampicillin can also producing organisms that include Haemophilus
be given intravenously. influenzae, Staphylococcus species, Escherichia
coli and Neisseria gonorrhea. The ampicillin-
Antipseudomonal Penicillins sulbactam combination (unasyn) is effective
against beta lactamase producing S. aureus and
As indicated by the name, antipseudomonal H. influenzae but not Serratia, which produces
penicillins are active against Pseudomonas beta lactamase that is not inhibited by sulbactam.
aeruginosa and other Gram-negative bacteria
such as Enterobacter species, Klebsiella species, Administration and Dosage
but they have no Gram-positive activity. Currently
most strains of Pseudomonas aeruginosa produce Besides oral and parenteral routes, penicillins
different types of beta lactamase. 11 As such can be administered by topical, subconjunctival
antipseudomonal penicillins are generally used in and intravitreal routes for the treatment of
combination with beta lactamase inhibitors for the ophthalmic infections. Ampicillin sodium,
treatment of pseudomonal infections.12 penicillin G, piperacillin and ticarcillin disodium
Carbenicillin indanyl sodium is acid-stable are available for ophthalmic use and their
available concentrations are listed under “drugs
and is administered orally. These drugs are widely
used in ocular therapeutics”. The dose of the
distributed in most body fluids like all penicillins.
penicillins depends on several factors including
High serum levels potentiate neurotoxicity
dosage form of the antibiotic, the type and
manifested as lethargy, neuromuscular irritability,
severity of the infection. Parenteral doses are
and seizures.
measured in units, with one unit equal to 0.6 mg
of standard penicillin, USP.
Beta Lactamase Inhibitors and Beta
Lactamase Inhibitor Combinations Therapeutic Uses
Beta lactamase inhibitors are clavulanic acid, Penicillins are useful in the treatment of many
sulbactam and tazobactam. These drugs are not acute ophthalmic bacterial infections and are
antibiotics. Although their structures resemble suited for surface application in the form of drops.
beta lactam molecules, they have negligible Only small quantities are needed; doses in the
antibacterial activity. They can inactivate many, order of 1,000 units are sufficient for effective
but not all beta lactamases thus can protect treatment. Penicillins used in the form of sodium
hydrolysable beta lactam antibiotics from being salt are well tolerated in the eyes, and can be used
destroyed by these enzymes. The addition of for subconjunctival injections as well intravenous
beta lactamase inhibitors extends the activity of or intramuscular injections.
As is the principle of anti-infective therapy, CEPHALOSPORINS
treatment with penicillins is successful only when
the primary infecting organism is sensitive to the The cephalosporins are beta lactam antibiotics
drug in therapeutic concentration. Organisms that have 7-aminocephalosporanic acid nucleus,
commonly found in ocular infections, which which resembles the 6-aminopenicillinic acid
are susceptible to the action of penicillin are of the penicillins (Fig. 8.6). The difference
Staphylococcus pyogenes, the hemolytic Strept between penicillins and cephalosporins is
ococcus, the Gonococcus and the Pneumo that the beta lactam ring of cephalosporin
coccus. bears the amino moiety at the 7th position
whereas, in penicillins, this moiety is attached
Types of Ocular Infection Suitable for to the 6th position. This difference makes the
Treatment by Penicillins cephalosporins more resistant to penicillinase
compared to penicillins.
1. Acute conjunctivitis, blepharitis and canali
culitis. Penicillin G potassium ophthalmic Classification
solution has been used, however, currently not
a favored choice in clinical practice due to its These drugs were first obtained from Cepha
narrow spectrum and instability. losporium acremonium, a fungus. The cephal
2. Chronic blepharitis due to S. aureus. Oxacillin osporins structures have now been modified
subconjunctival injections. to include various substitutions of their side
3. Keratitis and corneal ulcers caused by S. chains (R 1 and R 2) and have proliferated to
aureus. Oxacillin subconjunctival injections. four “generations”.15 In general Gram positive
4. Gonococcal conjunctivitis and gonococcal activity decreases from first generation to the
corneal ulcer. fourth and Gram negative activity increases in
5. Ocular syphilis. Acquired syphilis with a reverse order. Stability to beta lactamase also
ocular involvement should be treated as increases from the first to fourth generations
neurosyphilis with intravenous penicillin (Table 8.2.).
G. The dose is 18–24 million units (MU)
daily for 10 to 14 days, followed by procaine First Generation
penicillin, intramuscular, 2.4 MU weekly
First generation cephalosporins have the similar
for three weeks. 13 Treatment failure may
spectrums of activity as natural penicillins. They
occur if the patients initially are treated with
intramuscular penicillin, due to inadequate
intraocular concentrations.14
Adverse Effects
Penicillins are among the least toxic drugs known.
The most common side-effect of penicillins
is diarrhea. Nausea, vomiting, and epigastric
discomfort are also common. Penicillins can
cause immediate and delayed allergic reactions -
specifically, skin rashes, fever, and anaphylactic Figure 8.6 Cephalosporin structure showing:
shock. (a) Characteristic beta lactam ring; (b) Thiozolidine ring
Table 8.2 Classification of cephalosporins
Generation Drugs
First generation Cefalotin, cefazolin, cefapirin, cefacetrile, cefadroxil, cefalexin,

cefradine, cefaloridine, cefrezole
Second generation Cefaclor, cefuroxime, cefamandole, cefonicid, ceforanide, cefoxitin
Third generation Cefotaxime, ceftriaxone, cefixime, ceftizoxime, ceftibuten,
Basic third generation cephalosporins: cefpodoxime, cefteram
Third generation cephalosporins with Cefoperazone, ceftazidime
antipseudomonal acivity:
Fourth generation Cefclidine, cefepime, cefluprenam, cefpirome, cefozopran,
cefquinome.
possess excellent coverage against most Gram- Fourth Generation

positive pathogens but poor coverage against
most Gram-negative pathogens. Sensitive Gram- They are extended-spectrum agents with similar
positive bacteria include Group A streptococcal activity against Gram-positive organisms as the
pyogenes, beta lactamase producing and non- third-generation cephalosporins. They are highly
producing Staphylococcus aureus, Clostridium effective against Gram-negative organisms
perfringens, and many other strains of streptococci. such as P. aeruginosa, Enterobacteriaceae,
Haemophilus, Proteus and Neisseria.They also
Second Generation have a greater resistance to beta lactamases than
the third generation cephalosporins.
These agents are broad spectrum and are effec-
tive against Gram-positive and Gram-negative Pharmacokinetics
organisms. However, their activity against
Gram-positive organisms is less than that of the Besides oral and pareteral administration,
first-generation agents and their activity against cephalosporins can be administered by topical,
Gram-negative organisms is less than that of subconjunctival and intravitreal route for
the third-generation agents. Examples of Gram- the treatment of ophthalmic infections. The
negative organisms that are susceptible include formulations of cefazolin sodium, ceftazidime and
Neisseria gonorrhoea, Neisseria meningitidis, ceftriaxone available for ophthalmic use are listed
Haemophilus influenzae, Proteus and Enterobac under “drugs used in ocular therapeutics”. These
ter. They have no activity against Pseudomonas. drugs are widely distributed to most body tissues
Cefoxitin has greater activity towards anaerobes and fluids including aqueous humor.
such as Bacteroides fragilis compared to third- Overall, cephalosporins do not undergo
generation cephalosporins. metabolism and are excreted unchanged by
glomerular filtration and tubular secretion
Third Generation in urine. Some cephalosporins do, however,
Compared to the first generation, the third- undergo metabolism and their metabolites show
generation cephalosporins have better activity less antibacterial activity. Cefoperazone and
against Gram-negative organisms but are less ceftriaxone undergo billiary secretion, which
active against Gram-positive organisms with some makes them both, the choice in patients with renal
of them having activity against Pseudomonas. impairment.
Adverse Effects 6. Bacterial endophthalmitis: Usually combin

ation therapy of ceftazidime and vancomycin
Cephalosporins are generally a safe class of intravitreal.18
antibiotics. As in the case of penicillins, hyper 7. Pre-operative prophylaxis of post-operative
sensitivity can occur with cephalosporins, which
endophthalmitis: Second generation cephal
may range from mild allergic reaction that
osporins (cefuroxime) intracameral injection.19
manifest as an urticarial or a maculopapular
rash to a life-threatening reaction like-
anaphylaxis. Approximately, 20% of patients Carbapenems
with hypersensitivity to penicillins will also have
cross-reactivity with cephalosporins. Because This class of beta lactam antibiotics include
this cross-reactivity is not absolute, with caution,imipinem/cilastatin, meropenem, etarpenem,
cephalosporin can still be administered to patients doripenem, panipenem, biapenem, razupenem and
with a history of hypersensitivity reactions to are derived from thienamycin, naturally obtained
penicillins. from Streptomyces cattleya. The prototype drug
is imepenem. The antibacterial activity of the
Therapeutic Uses carbepenems includes both, Gram-positive and
Gram-negative organisms such as Streptococcus,
Types of Ocular Infection Suitable for Staphylococcus, Listeria, Pseudomonas and
Treatment by Cephalosporins Acinetobacter. They are also effective against
1. Acute conjunctivitis and blepharitis anaerobes, including20 Clostridium difficile and
caused by Gram-positive flora (S. aureus, Bacteroides fragillis. This drug class is resistant
Streptococcus species): Topical first generation to most beta lactamases.
cephalosporins (cefazolin).
2. Gonococcal conjunctivitis and gonococcal Pharmacokinetics
corneal ulceration: Basic third generation Carbapenems are administered intravenously and
cephalosporins (ceftriaxone, cefotaxime) are not absorbed orally. They penetrate well into
intramuscularly or intravenously. In the only aqueous humor and vitreous.21
published study by Haimovici and Roussel, Imipenem is hydrolyzed by an enzyme
a single 1 gram intramuscular injection of found in renal tubules, dehydropeptidase and
ceftriaxone was used in the treatment of produces nephrotoxic metabolites. It is marketed
gonococcal conjunctivitis.16 in combination with cilastatin, a drug that
3. Bacterial keratitis and corneal ulceration inhibits dehydropeptidase. This combination
due to Gram-positive flora: First generation does not increase the plasma levels of imipenem
cephalosporins (cefazolin) by subconjunctival but significantly reduces the nephrotoxic
injections. metabolites. It has a half life of proximately 1
4. Pseudomonal keratitis and corneal ulceration: hour. Imipenem is largely excreted unchanged
Third and fourth generation cephalosporins in urine and a small amount into the bile, which
with antipseudomonal activity (ceftazidime, is insufficient to disturb the normal flora of the
cefipime), subconjunctival injections or colon. Although cilastatin is also excreted by the
systemic (intramuscular and intravenous) kidneys, only imipenem is cleared by extra-renal
injection in case of corneal perforation. mechanisms. Therefore, in patients with renal
5. Dacryocystitis and dacryoadenitis: Second impairment, a dose adjustment may be necessary.
and third generation cephalosporins intrave- Both drugs are cleared by hemodialysis and
nously.17 hemofiltration.
Adverse Effects OXACEPHEMS

Imipenem causes thrombophlebitis on Oxacephems are synthetic drugs and include
intravenous administration. It can also cause moxalactam and flomoxef. They have a
nausea and vomiting. Some metabolites of molecular structure similar to cephalosporin core
imipenem are neurotoxic with effects such as and, therefore, they are usually grouped with
tremor, seizure and confusional state. It can also cephalosporins. Their mechanism of action is
cause fits but this is usually seen in patients with the same as that of other beta lactams. Antibiotic
pre-existing CNS disease or patients with renal spectrum and therapeutic uses are similar to
failure and excessively high levels of imipenem the third generation cephalosporins and include
metabolites. both Gram-positive and Gram-nagative bacteria.
Moxalactam can induce hemopoietic disturbances
Therapeutic Uses like hypoprothrombinemia, thrombocytopenia and
platelet dysfunction, which may result in bleeding.
Carbapenems are administred intravenously
and are used in the treatment of severe ocular
infections such as bacterial endophthalmitis. They Non beta lactam antibiotics
also may be used as pre-operative prophylaxis
of post-operative endophthalmitis and in the Chloramphenicol
treatment of orbital cellulitis.22 Chloramphenicol was introduced more than 50
years ago. It was derived from the bacterium
MONOBACTAMS Streptomyces venezuelae, though now it is
produced synthetically. Chloramphenicol is
These are the drugs with a monocyclic beta lactam a neutral and stable compound. The formal
ring. The prototype is aztreonam. Its mechanism chemical name (IUPAC) is 2, 2-dichloro-N-
of action is similar to other beta lactams. It is ((1R,2R)-1, 3-dihydroxy-1-(4-nitrophenyl)
beta lactamase resistant and is highly effective propan-2-yl) acetamide. The structure activity
against most Gram-negative aerobes, including relationship of chloramphenicol mandates that
Pseudomonas aeruginosa, Escherichia coli, not many changes can be made to the molecule.
Klebsiella, and Enterobacter. Due to its specific The aromatic ring is essential for the activity of
spectrum of activity, aztreonam does not disturb the agent. The structure is as shown in Figure 8.7.
the normal Gram-positive and anaerobic intestinal
flora. Mechanism of Action
Like imipenem, aztreonam is not absorbed Chloramphenicol is a bacteriostatic antibiotic. It
orally. It is given either intramuscularly or inhibits bacterial protein synthesis. It binds to the
intravenously. It is largely excreted unchanged by 50S ribosomal subunit and inhibits the activity of
the kidneys. It is widely distributed throughout the the enzyme, peptidyl transferase. This results in
body. The clinical uses of aztreonam include severe inhibition of peptidyl tRNA at the donor site ‘P’
ocular infections such as bacterial endophthalmitis from “donating” the growing peptide chain to
caused by Gram-nagative bacteria including aminoacyl t-RNA at the acceptor site ‘A’, hence
Pseudomonas aeruginosa resistant to other preventing elongation of peptide chain (Fig. 8.8).
beta lactam antibiotics. Aztreonam has a little There is some evidence that chloramphenicol
allergic cross-reactivity with beta lactams (except inhibits protein synthesis in rapidly proliferating
ceftazidime) and may be used in case of a prior mammalian cells, which may be the cause of
allergic reaction.23 reversible bone marrow suppression.
Antibacterial Spectrum Pharmacokinetics

Chloramphenicol exerts bacteriostatic effect on a Chloramphenicol is uncharged and neutral. It is
wide range of Gram-positive and Gram-negative also relatively water soluble and is well absorbed.
organisms and is active against Rickettsia species, It penetrates well into the aqueous humor after
Chlamydia species and Mycoplasma species. It topical application.24 After oral administration of
is particularly effective against H. influenzae, chloramphenicol palmitate, it is rapidly absorbed
S. pneumoniae, S. typhi, Neisseria meningitidis, as free chloramphenicol. The peak serum level
Neisseria gonorrhoeae, Brucella species and after an oral dose of chloramphenicol is acheived
Bordetella pertussis. in 1 to 3 hours. Chloramphenicol sodium succinate
Acquired resistance to chloramphenicol is is hydrolyzed to free chloramphenicol following
very common. Usually it is caused by plasmid- intravenous administration, by esterases in the
mediated production of acetyltransferase. These liver, kidneys and lungs. The rate and extent of
inactivating enzymes decrease chloramphenicol’s hydrolysis and renal elimination of the succinate
ability to bind to the bacterial ribosomes. Another ester are subject to a high degree of interindividual
mechanism of resistance is decreased permeability variation. The palmitate and sodium succinate
into the bacterial cell. Both natural and acquired esters are inactive until hydrolyzed to free
resistance to chloramphenicol has been seen chloramphenicol, which occurs rapidly in vivo.
in strains of P. aeruginosa, Staphylococccus, Chloramphenicol is approximately 60%
and Enterobacteriaceae particularly Shigella, protein bound. It is widely distributed in the
Salmonella, and Escherichia. body. An important aspect of chloramphenicol’s
distribution is that it is able to penetrate blood
ocular barrier. The drug crosses the placenta and
is distributed into the breast milk.
Chloramphenicol is metabolized in the
liver, mainly by conjugation with glucuronic
acid; only about 5 to 15% of an oral dose is
excreted unchanged in the urine. The half-life
of chloramphenicol is 1.5 to 4 hours in adults.
The plasma half-life is increased in patients with
Figure 8.7 Structure of chloramphenicol
(C11H12Cl2N2O5) markedly reduced hepatic function. In patients
Figure 8.8 Mechanism of action of chloramphenicol

with impaired renal function, the half-life of serious adverse effect is the non-dose dependent
chloramphenicol itself is not significantly altered aplastic anemia, which can occur with systemic
although the half-life of the inactive metabolites or topical therapy. Although rare (1:25,000 to
may be prolonged. Since the processes for 40,000), it is a serious adverse event as it is
glucuronide conjugation and renal excretion in irreversible and may be fatal. It is probably an
neonates may be immature, the half-life of the idiosyncracy that can occur anytime during
drug in neonates less than 3 days old may be in treatment or weeks and even months after
excess of 24 hours and about 10 hours for infants treatment. Although non-dose dependent, it occurs
10–16 days old. In these cases the dosage and more with prolonged or repetitive treatment. It is
administration interval should be adjusted using more common with doses exceeding 4 g daily
measured serum concentrations. or a plasma concentration exceeding 25 mg/
mL. Despite the risk of aplastic anemia, it is
Therapeutic Uses not contraindicated in patients with serious
infections requiring chloramphenicol treatment.
Chloramphenicol’s spectrum of activity covers
The drug should, however, be discontinued if
the majority of ocular pathogens. In a study of
reticulocytopenia, leukopenia, thrombocytopenia,
738 patients with acute bacterial infections of
anemia or other hematologic abnormalities occur.
the external eye, there was an overall resistance
Doona and Walsh recommended that the
rate of only 6% to chloramphenicol, compared
topical use of chloramphenicol should be
to 9% with tetracycline and around 20% to the
restricted due to the possibility of systemic blood
aminoglycosides tested.25
dyscrasias.26 A large number of ophthalmologists
Chloramphenicol is, in many ways, an ideal and hematologists countered this view and
drug for topical use. It penetrates well into the highlighted the extremely large number of
aqueous humor after topical application and has prescriptions of chloramphenicol dispensed, the
low ocular surface toxicity. The use of systemic small number of blood dyscrasias reported and
chloramphenicol is reserved for the treatment the lack of proof of causality in these cases. The
of serious infections caused by susceptible evidence for and against this association has been
organisms when less toxic antimicrobials are reviewed.27 Walker et al. measured serum levels
ineffective or contraindicated. of chloramphenicol in subjects after 1–2 weeks
of treatment with four times daily instillation.
Types of Ocular Infections Suitable for They found that serum levels did not accumulate
Treatment by Chloramphenicol to detectable levels of 1 mg/L and concluded that
topical chloramphenicol did not present a risk of
1. Acute bacterial conjunctivitis and blepharitis.
inducing dose-related bone marrow toxicity.28
2. Gonococcal conjunctivitis and gonococcal
Lancaster et al. used the general practice
corneal ulcer. Chloramphenicol is used as
research database to describe prescribing patterns
an alternate for the treatment of gonococcal
of chloramphenicol eyedrops and to estimate
infection when the cephalosporins or penicillin
the risk of aplastic anemia after their use. Three
are not suitable.
patients with serious hematological toxicity and
3. Bacterial keratitis and corneal ulceration.
one who developed mild, transient leukopenia
4. Dacryocystitis and dacryoadenitis.
that was not considered serious were identified
among the 442,543 patients who received 674,148
Adverse Effects prescriptions for chloramphenicol eyedrops.
Chloramphenicol can cause two types of The researchers concluded that, even in the
hematological effects, a dose-dependent and a unlikely event that all three cases were caused by
non-dose dependent one. Of the two, the more chloramphenicol eyedrops, these data indicated
that the risk of serious hematological toxicity it should not be used in nursing mothers because
after treatment with ocular chloramphenicol of the possibility of adverse effects in the infant.
was small.29 Wilholm et al. also concluded that
data provided no support for the claim that Interactions
chloramphenicol eyedrops increased the risk of
Chloramphenicol inhibits hepatic microsomal
aplastic anemia.30
enzymes and may interfere with the metabolism
Although, the risk of aplastic anemia due to
of alfentanil, chlorpropamide, phenobarbital,
topical application of chloramphenicol is not well
phenytoin, tolbutamide, warfarin or other
founded, it is very important to monitor the blood
drugs metabolized by the microsomal system.
count during the chloramphenicol treatment.
Dosages of these drugs may need to be adjusted
Nausea, vomiting and diarrhea occurring early
accordingly. Conversely, drugs such as rifampin
in the course of treatment are commonly due to
or phenobarbital, which induce microsomal
gastrointestinal tract mucosal irritation. However,
enzymes may increase the metabolism and
if these symptoms are prolonged or if the onset
reduce serum concentrations of chloramphenicol.
occurs later in therapy, they must be investigated
Chloramphenicol may prolong the prothrombin
to rule out superinfection.
time in patients receiving anticoagulant therapy
Optic and peripheral neuritis have been by interfering with vitamin K production by
reported, usually following long-term therapy. intestinal bacteria.
If this occurs, the drug should be promptly Concurrent therapy with chloramphenicol may
discontinued. delay the clinical response to iron preparations,
Fever, macular and vesicular rashes, angio vitamin B 12 or folic acid in the treatment
edema and urticaria may occur, especially of anemias. Concomitant administration of
after topical use. A toxic reaction can occur in chloramphenicol in patients receiving radiation
premature and newborn infants receiving large therapy or myelosuppressive drugs may result in
doses of chloramphenicol. It is characterized additive bone marrow suppression.
by abdominal distention, vomiting, blue-gray Chloramphenicol has been reported to
skin color, hypothermia, irregular breathing and antagonize the bactericidal activity of penicillins
cardiovascular collapse, followed by death in and aminoglycosides in vitro and some clinicians
few hours or days. If chloramphenicol is stopped recommend that these antibiotics not to be used
early after the onset of symptoms, the infant may concomitantly. However, in vivo antagonism has
recover completely. not been demonstrated and chloramphenicol has
been used successfully with ampicillin, penicillin
Contraindications G or aminoglycosides with no apparent decrease
in activity.
Chloramphenicol is contraindicated in individuals
with a history of previous hypersensitivity or toxic
reaction to it. As chloramphenicol readily crosses QUINOLONES AND
the placenta, it should be used with caution in FLUOROQUINOLONES
pregnant women although birth defects in humans
have not been documented. However, it should The first quinolone, nalidixic acid was introduced
not be used in pregnancy at term or during labor into the clinical practice in 1962 by Lescher and
because of potential toxicity in premature or colleagues. The fluoroquinolones are a relatively
full-term infants, including gray baby syndrome. new group of synthetic antibiotics, first introduced
Chloramphenicol should not be used in premature in 1986. They are derivatives of quinolones which
and full-term infants for the same reasons. As have a fluorine atom attached to the central ring,
chloramphenicol is excreted in human breast milk, typically at the C-6 or C-7 position (Fig. 8.9.)
Classification have broader clinical applications in the treatment

of complicated urinary tract infections and
Quinolones and fluoroquinolones are divided into pyelonephritis, sexually transmitted diseases,
four generations (Table 8.3). selected pneumonias and skin infections.
Ciprofloxacin is the most potent fluoroquinolone
First Generation against P. aeruginosa. Ciprofloxacin and ofloxacin
The first generation agents are the oldest and are the most widely used second generation
least often used quinolones. These drugs had quinolones because of their availability in oral,
poor systemic distribution and limited activity intravenous and topical formulations and their
and were used primarily for Gram-negative broad set of FDA-labeled indications.
urinary tract infections. Cinoxacin and nalidixic
acid require more frequent dosing than the newer Third Generation
quinolones, and they are more susceptible to the The third generation fluoroquinolones have
development of bacterial resistance. expanded activity against Gram-positive
organisms, particularly penicillin-sensitive and
Second Generation penicillin-resistant S. pneumoniae, and atypical
The second generation fluoroquinolones have pathogens such as Mycoplasma pneumoniae
increased Gram-negative activity, as well as some and Chlamydia pneumoniae. Although the third-
Gram-positive and atypical pathogen coverage. generation agents retain broad Gram-negative
Compared with first generation quinolones, coverage, they are less active than ciprofloxacin
besides the use in ocular infections, these drugs against Pseudomonas species. Besides their
extensive use in the treatment ocular infections
in topical formulation, they are also useful in the
treatment of community-acquired pneumonia,
acute sinusitis and acute exacerbations of chronic
bronchitis.
Fourth Generation
Figure 8.9 Essential structure of all quinolone antibiotics: The fourth generation fluoroquinolones have
The R shown in bold is usually piperazine; if the molecule
contains fluorine, it is a fluoroquinolone. significant antimicrobial activity against anaerobes
while maintaining the Gram-positive and Gram-
Table 8.3 Classification of fluoroquinolones negative activity of the third generation drugs.
They also retain activity against Pseudomonas
Generation Drugs species comparable to that of ciprofloxacin.
First generation Nalidixic acid, cinoxacin, They are available in topical formulation for the
oxolinic acid, pipemidic acid treatment of ocular infections.
Second generation Ciprofloxacin, ofloxacin,
norfloxacin, pefloxacin,
enoxacin, lomefloxacin
Mechanism of Action
Third generation Levofloxacin, sparfloxacin, Fluoroquinolones are the only class of
gatifloxacin antimicrobial agents in clinical use that are
Fourth generation Moxifloxacin, gemifloxacin, direct inhibitors of bacterial DNA synthesis.
trovafloxacin Fluoroquinolones inhibit two bacterial
enzymes, DNA gyrase (topoisomerase II) and Therapeutic Uses
topoisomerase IV. DNA gyrase is an essential
enzyme involved in the replication, transcription The newer fluoroquinolones have a wider clinical
and the repair of damaged DNA. Topoisomerase use and a broader spectrum of antibacterial
IV is involved in the separation of chromosomal activity including Gram-positive and Gram-
DNA during cell division. Both enzymes, DNA negative aerobic and anaerobic organisms and
gyrase and topoisomerase IV, have essential and have become available for ophthalmic use.
distinct roles in DNA replication. Topoisomerase
IV is the primary quinolone target in Gram- Types of Ocular Infection Suitable for
positive bacteria, while DNA gyrase is primarily Treatment by Fluoroquinolones
inhibited by quinolones in Gram-negative
1. Acute bacterial conjunctivitis and blepharitis.
microbes.31
Second generation fluoroquinolones are very
The quinolones bind to the complex of each
effective in the treatment of acute bacterial
of these enzymes with DNA; the resulting
conjunctivitis and blepharitis. Ciprofloxacin
complexes, including the drug, block progress of
has been compared with chloramphenicol and
the DNA replication enzyme complex. Finally,
tobramycin in the treatment of conjunctivitis
this action results in damage to bacterial DNA
and blepharitis. Power et al. investigated the
and bacterial cell death. Thus, fluoroquinolones
efficacy of ciprofloxacin and chloramphenicol
are bactericidal agents.
in 57 culture-positive patients and reported
that the difference between the groups was
Pharmacokinetics not significant. 34 Safety was also similar,
with only one patient from each treatment
Fluoroquinolones available for treatment of
group suffering an adverse event. Liebowitz
ophthalmic infections are listed under “drugs compared ciprofloxacin with tobramycin
used in ocular therapeutics”. Oral absorption in a placebo controlled trial of 288 culture-
of fluoroquinolones is good but is diminished positive patients with bacterial conjunctivitis.
by coadministration of cations (aluminum, Mg, Both antibiotics were highly effective and
Ca, zinc, and iron preparations). After oral and significantly superior to placebo.35
parenteral administration, fluoroquinolones are 2. Gonococcal conjunctivitis and gonococcal
widely distributed in most extracellular and corneal ulcer. Second generation fluoro
intracellular fluids and are concentrated in the quinolones (ciprofloxacin) are used topically
prostate, lungs, and bile. and parenterally in the treatment of gonococcal
Fluoroquinolones penetrate well into the conjunctivitis and keratitis.
aqueous humour after topical application. 32 3. Bacterial keratitis and corneal ulceration. The
Moxifloxacin 0.5% has better corneal penetration common pathogens causing bacterial keratitis
compared to gatifloxacin 0.3%. Moxifloxacin are Pseudomonas aeruginosa, Pneumococcus,
0.5 % achieves highest level in aqueous humor Moraxella species, and Staphylococci.
followed by gatifloxacin 0.3% and ciprofloxacin Fluoroquinolones such as levofloxacin
0.3%. Compared to ofloxacin 0.3%, levofloxacin 0.5%, ofloxacin 0.3%, norfloxacin 0.3%, or
0.5% has better ocular penetration. Levofloxacin ciprofloxacin 0.3% are commonly used as first-
1.5% better penetrates the corneal tissue and line agents to treat this condition as long as
aqueous compared to gatifloxacin. 33 Most local prevalence of resistant organisms is low.36
fluoroquinolones are metabolized in the liver If the pathogen identified is Mycobacteria,
and excreted in urine, reaching high levels in the fourth-generation fluoroquinolones
urine. Moxifloxacin is eliminated primarily in (moxifloxacin 0.5% and gatifloxacin 0.3%) are
bile. indicated. In a prospective, multicenter clinical
study, the clinical and antibacterial efficacy
sensation, itching, conjunctival hyperemia and
of ciprofloxacin 0.3% with that of standard transient burning. The frequencies of occurrences
dual therapy in 148 culture proven cases of with individual fluoroquinolone are as tabulated
bacterial keratitis was compared. Most patients
in Table 8.4.
in the standard dual therapy group received One of the untoward ocular events associated
cefazolin 3.3% with gentamicin or tobramycin with ciprofloxacin therapy was a white crystalline
1.4%. Success rates were similar at 92% for precipitate, commonly located in the superficial
ciprofloxacin and 88% for the dual therapy.35portion of the corneal defect (i.e. the area of
4. Bacterial endophthalmitis. inflammation). This problem was encountered in
5. Pre-operative prophylaxis for post-operative 16.6% of patients. A group of ophthalmologists
endophthalmitis. Fluoroquinolones are the involved in the multicenter study noted the
drug of choice in the prophylaxis of post appearance of the white precipitate as the only
operative endophthalmitis. In contrast with potential adverse effect in the ciprofloxacin
group.38 Although, the precipitate resolved in all
cephalosporines, that are used as intracameral
injection, fluoroquinolones are used as topical
patients and did not appear to cause any scarring,
ophthalmic solution.37 they saw it as a disadvantage because it caused
a temporary decrease in vision and prevented
Adverse Effects adequate evaluation of the corneal infiltrate.
Precipitation of ciprofloxacin occurs as a result
The fluoroquinolones as a class are generally of change in the pH of the eyedrop as it mixes
well tolerated. Most adverse effects are mild with the tear film.39
in severity, self-limited, and rarely result in
treatment discontinuation. Some of the adverse Phototoxicity
effects are outlined below.
Exposure to ultraviolet rays from direct or indirect
sunlight should be avoided during treatment and
Local Adverse Reactions
for several days (5 days with sparfloxacin) after
Local adverse effects following ocular admin the use of the drug. The degree of phototoxic
istration of fluoroquinolones include pain or potential of fluoroquinolones is as follows:
discomfort in the eye, swelling, foreign body lomefloxacin > sparfloxacin > ciprofloxacin
Table 8.4 Prevalence of adverse effects of fluoroquinolones
Adverse effects Local Dis- Local Sensation of Itching Conjucntival Burning

comfort edema foreign body hyperemia
Drugs or pain
Ciprofloxacin29 2% < 1% < 10% < 10% < 10% Reported
Ofloxacin 0.3% Reported Reported Reported Reported Reported Reported
(Ocuflox)34
Levofloxacin 0.5% 1–3% < 1% 1–3% < 1% Not reported 1–3%
(Quixin)31
Levofloxacin 1.5% 1–2% < 1% Not reported Not Not reported 1–2%
(Iquix)31 reported
Gatifloxacin 0.3% 1–4% 1–4% Not reported 1–4% 1–4% 1–4%
(Zymar)30
Moxifloxacin 0.5% 1–6% Not Not reported 1–6% 1–6% 1–6%
(Vigamox)31 reported
> norfloxacin = ofloxacin = levofloxacin = Recently, rare cases of hypoglycemia have
gatifloxacin = moxifloxacin. been reported with gatifloxacin and ciproflox
acin in patients also receiving oral antidiabetic
Systemic Adverse Reactions medications, primarily sulfonylureas. Although
hypoglycemia has also been reported with other
The most common adverse events experienced fluoroquinolones (levofloxacin and moxifloxacin),
with oral fluoroquinolone administration are the effects have been mild.
gastrointestinal such as nausea, vomiting, Hypersensitivity reactions occur only occa
diarrhea, constipation, and abdominal pain, which siona lly during quinolone therapy and are
occur in 1 to 5% of patients. generally mild to moderate in severity, and usually
Headache, dizziness, and drowsiness have resolve after treatment is stopped.
been reported with all fluoroquinolones. Insomnia
was reported in 3–7% of patients with ofloxacin.
Contraindications
Severe CNS effects, including seizures, have
been reported in patients receiving trovafloxacin. Contraindications include previous allergic
Seizures may develop within 3 to 4 days of therapy reaction to ciprofloxacin or other quinolones and
but resolve with drug discontinuation. Although certain disorders that predispose to arrhythmias
seizures are infrequent, fluoroquinolones should such as QT-interval prolongation, uncorrected
be avoided in patients with a history of convulsion, hypokalemia or hypomagnesemia, significant
cerebral trauma, or anoxia. No seizures have bradycardia.
been reported with levofloxacin, moxifloxacin, Fluoroquinolones are approved for use only
gatifloxacin, and gemifloxacin. With the older non- in people older than 18 years of age. They are
fluorinated quinolones neurotoxic symptoms such contraindicated in children and in pregnant
as dizziness occurred in about 50% of the patients. women because they may cause cartilage lesions
C o n c e r n a b o u t t h e d e v e l o p m e n t o f if growth plates are open. However, some experts,
musculoskeletal effects, evident in animal studies, who challenge this view because evidence is weak,
has led to the contraindication of fluoroquinolones have recommended prescribing fluoroquinolones
for routine use in children and in women who are as a 2nd-line antibiotic and restricting use to
pregnant or lactating. a few specific situations with severe and life-
Although fluoroquinolone-related tendinitis threatening infections. The safety and efficacy of
generally resolves within one week of discont fluoroquinolone eyedrops in children under the
inuation of therapy, spontaneous ruptures have age of one year has not been established.
been reported as long as nine months after cessation Fluoroquinolones are assigned to pregnancy
of fluoroquinolone use. Potential risk factors for risk category C (FDA), indicating that these
tendinopathy include age > 50 years, male gender, drugs have the potential to cause teratogenic or
and concomitant use of corticosteroids. embryocidal effects. Giving fluoroquinolones
Trovafloxacin use has been associated with during pregnancy is not recommended unless
rare liver damage, which prompted the withdrawal the benefits justify the potential risks to the fetus.
of the oral preparations from the US market. These agents are also excreted in breast milk and
However, the IV preparation is still available for
should be avoided during breast-feeding.
treatment of infections so serious that the benefits
outweigh the risks.
The newer quinolones have been found to Interactions
produce additional toxicities to the heart that were Ciprofloxacin is a potent inhibitor of cytochrome
not found with the older compounds. Evidence P450 and may interfere with the metabolism of
suggests that sparfloxacin and grepafloxacin may chlorpropamide, phenytoin, tolbutamide, warfarin,
have the most cardiotoxic potential. theophylline and other drugs metabolized by the
microsomal system. Dosages of these drugs by active (energy-dependent) transport across the
may need to be adjusted accordingly. The inner cytoplasmic membrane. Uptake into Gram-
use of fluoroquinolones with drugs known to positive bacteria, such as Bacillus anthracis (the
prolong the QT interval or to cause bradycardia causative agent of anthrax), occurs similarly via
(e.g. metoclopramide, cisapride, erythromycin, an energy-dependent transport system. In contrast,
clarithromycin, classes Ia and III antiarrhythmics, mammalian cells lack the active transport system
tricyclic antidepressants) will increase the risk or found in susceptible bacteria.
worsen their cardiovascular adverse effects. Once in the cell, tetracycline binds reversibly
to the 16S rRNA on the 30S ribosomal subunit
and inhibits protein synthesis by blocking the
TETRACYCLINES binding of aminoacyl tRNA to the A-site on the
Tetracyclines were discovered in the 1950s. Their mRNA-ribosome complex. This action prevents
antimicrobial spectrum was broader than any the addition of further amino acids to the
other antibiotic known at that time. The individual nascent peptide. However, inhibition of protein
tetracyclines differ in pharmacokinetic properties synthesis does not account entirely for the high
such as absorption, tissue distribution and bacterial selectivity of tetracyclines, because
elimination. Presently, the name “tetracycline” these drugs can also halt eukaryotic protein
refers to a group of antibiotics of either natural synthesis in vitro at low concentrations. The
(derived from a species of Streptomyces), or semi- active accumulation of these drugs in bacteria
synthetic origin with a similar basic structure of but not in mammalian cells allows for high
four linearly annealed six-membered rings (Fig. selectivity of tetracyclines.
8.10).
Classification (Table 8.5)
Mechanism of Action
Antibacterial Activity
Tetracycline is a group of broad spectrum
Tetracyclines are characterized by their exceptional
antibiotics that inhibit bacterial protein synthesis
chemotherapeutic efficacy against a wide range
and are bacteriostatic. Tetracycline must first gain
of Gram-positive and Gram-negative bacteria,
entry into the bacterial cell; either by passive
Rickettsia, Spirochetes, and large viruses, such as
diffusion through hydrophilic pores present on
members of the lymphogranuloma group. The list
bacterial cellular membrane or by active uptake,
of antibacterial activity of tetracyclines includes:
requiring energy. Tetracyclines enter Gram-
Gram-positive cocci (Staphylococcus species
negative bacteria by passive diffusion through
and Streptococcus species)
porin proteins in the outer membrane, followed
Gram-negative cocci (Neisseria gonorrhoeae).
Gram-positive bacilli (Bacilus anthracis,
Table 8.5 Classification of tetracyclines
Naturally occurring Semi-synthetic

Tetracycline Doxycycline
Chlorotetracycline Minocycline
Oxytetracycline Methacycline
Demeclocycline Rolitetracycline
Figure 8.10 Basic structure of tetracycline consists of Tigecycline
four rings
Corynebacterium diphtheriae, Clostridia tissue. Tetracycline and minocycline are excreted
tetani and others) primarily in the urine and doxycycline undergoes
Gram-negative bacilli (Haemophilus influenzae, billiary excretion. Tetracycline is available as
Helicobacter pylori) eyedrop and ointment.
Atypical bacteria (Chlamydia species Mycoplasma
species, Legionella species, Ureaplasma) Therapeutic Uses
Spirochetes (Treponema pallidum, Borrelia
recurrentis, Borrelia burgdorferi) Types of Ocular Infection Suitable for
Rickettsiae Treatment by Tetracyclines
Listeria species
1. Acute conjunctivitis and blepharitis.
Vibrio cholera
2. Ophthalmia neonatorum. Tetracycline ointment
Anaerobes (Bacteroides species, Propionibac
1% is used in prevention and treatment of
terium, Peptococcus).
gonococcal and chlamydial ophthalmia
neonatorum (neonatal conjunctivitis).41,42
Bacterial Resistance 3. Trachoma. Doxycycline and tetracycline are
Since the bacterial selectivity of tetracyclines the first line drugs in the treatment of trachoma.
results from drug-concentrating mechanisms, it 4. Bacterial keratitis and corneal ulceration due to
follows that resistance can occur through increased Gram-positive flora (Staphylococcus species).
drug efflux or decreased drug influx. In fact, Tetracyclines are used as an alternative
plasmid-encoded efflux pumps represent the most treatment, usually in cases of allergic reaction
widespread mechanism employed by tetracycline- to other antibiotics.
resistant microbes. A second form of resistance 5. Dacryocystitis and dacryoadenitis. Tetracycline
arises through the production of proteins that is used as alternative to other antibiotics.
interfere with the binding of tetracyclines to the 6. Bacterial endophthalmitis.
ribosome. Yet a third mechanism is the enzymatic
inactivation of tetracyclines. Adverse Effects
Because of the development of strains of
microorganisms resistant to the tetracyclines, Common side-effects associated with tetracyclines
these antibiotics have lost some of their usefulness. include cramps or burning of the stomach,
They are no longer the drugs of first choice for diarrhea, sore mouth or tongue. Tetracyclines
the treatment of staphylococcal, streptococcal, or should not be used in children under the age of
pneumococcal infections.40 8 years, and specifically during periods of tooth
development.
Tetracyclines are classed as pregnancy category
Pharmacokinetics D (there is evidence of human risk, but clinical
About 60 to 80% of tetracycline and ≥ 90% of benefits may outweigh risk). Tetracyclines cross
doxycycline and minocycline are absorbed after the placenta, enter fetal circulation, accumulate
oral use. Absorption is decreased by metallic in fetal bones, and, if used during the 2nd or 3rd
cations (e.g. Al, Ca, Mg, Fe); thus, tetracyclines trimester, may cause permanent discoloration
should not be taken with preparations containing of teeth and alterations in bone development.
these substances such as antacids, many vitamin Tetracyclines enter breast milk, but usually in
and mineral supplements. Food decreases small amounts (particularly tetracycline). Use
absorption of tetracycline but not of doxycycline during breast feeding is usually discouraged.
or minocycline. Tetracyclines penetrate into Excessive blood levels due to use of high
most body tissues and fluids and tetracycline doses or renal insufficiency may lead to fatal
particularly penetrates well into the ocular acute fatty degeneration of the liver, especially
during pregnancy. Minocycline commonly causes
vestibular dysfunction, particularly in women,
limiting its use. Use of minocycline has also been
associated with development of autoimmune
disorders such as SLE and polyarteritis nodosa,
which may be reversible.
Tetracycline can exacerbate azotemia in
patients with renal insufficiency. Expired
tetracycline capsules can degenerate and, if
ingested, cause Fanconi syndrome. Patients
should be instructed to discard the expired drug.
Other side-effects include, candidiasis,
Clostridium difficile-induced diarrhea
(pseudomembranous colitis) and if not
swallowed with water, tetracycline can cause
esophageal erosions. Tetracyclines can cause
skin photosensitivity, which increases the risk
of sunburn upon exposure to UV light. Rarely,
tetracyclines may cause allergic reactions. Very
Figure 8.11 Chemical structure of macrolides
rarely severe headache and vision problems may
be signs of dangerous secondary intracranial
hypertension.
bonds between the amino acids. In addition to
inhibition of peptide bond formation, macrolides
MACROLIDES also prevent the translocation of peptidyl tRNA
Macrolides are products of Actinomycetes from the A-site to the P-site thus blocking
(soil bacteria) or semi-synthetic derivatives of the elongation of growing peptide chain of
them. The prototype drug, erythromycin, which sensitive microorganisms. Their binding site is
consists of two sugar moieties attached to a 14- either identical or in close proximity to that for
atom lactone ring, was obtained in 1952 from clindamycin and chloramphenicol.
Streptomyces erythreus. Clarithromycin and
azithromycin are semi-synthetic derivatives of Antibacterial Spectrum
erythromycin (Fig. 8.11). The macrolides have an antimicrobial spectrum
similar to or slightly wider than that of penicillin,
Classification and are often used for patients allergic to
According to their chemical structure macrolides penicillins. They are effective against Gram-
may be divided into 14-membered, 15-membered positive organisms especially Streptococcus
and 16-membered structures (Table 8.6).43 species Staphylococcus species (except MRSA),
and Corynebacteria diphtheriae.
In contrast to beta lactams they are active
Mechanism of Action against atypical organisms, such as Myco
Erythromycin and other macrolide antibiotics plasma species, Chlamydia species (including
inhibit protein synthesis by binding reversibly Chlamydia trachomatis, C. psittaci, C. pneu
to the 23S rRNA molecule on the 50S subunit of moniae), Legionella species, Listeria and
the bacterial ribosome. They inhibit the enzyme Ureaplasma urealyticum.44 Certain mycobacteria
peptidyltransferase from forming the peptide (Mycobacterium kansasii, M. scrofulaceum) are
Table 8.6 Classification of macrolides
14-Membered 15-Membered (Azalides) 16-Membered

Naturally occurring Naturally occurring Naturally occurring
Erythromycin — Spiramycin
Midecamycin
Josamycin
Semi-synthetic Semi-synthetic Semi-synthetic
Clarithromycin Roxithromycin Azithromycin Midecamycin acetate
also susceptible. Gram-negative organisms such tissue. The tissue concentration of macrolide
as Neisseria, Bordetella pertussis, Bartonella can be 10–200 times higher than in plasma. The
henselae, B. quintana, some Rickettsiae species, ability for azithromycin to accumulate in tissues,
Treponema pallidum, and Helicobacter pylori are which act as a reservoir, provides post antibiotic
susceptible. However, Haemophilus influenzae is effect of azithromycin. 48 Macrolides tend to
somewhat less susceptible.45 accumulate within leukocytes, and are, therefore,
actually transported into the site of infection.49
Bacterial Resistance Gram-positive bacteria accumulate erythromycin
about 100 times more than do the Gram-negative
There are a few mechanisms by which micro microorganisms. The non-ionized form of the
organisms can become resistant to macrolides. drug is considerably more permeable to cells, and
The most common are altered binding site and this probably explains the increased antimicrobial
active efflux of antibiotic.46 The active efflux of activity observed in alkaline pH.
antibiotic (plasmid-mediated) is mostly associated Macrolides are metabolized by the cytochrome
with Gram-positive bacteria and may be overcome P450 in liver and their elimination is mainly
by high doses of macrolides. Mutational changes through bile, although, some undergo renal
of the 23S ribosomal RNA of the 50S ribosomal excretion.
subunit, which may be chromosomal, plasmid or
on a transposon can also result in failure of drug
Therapeutic Uses
binding.
Types of Ocular Infection Suitable for
Pharmacokinetics Treatment by Macrolides
Macrolides are usually administered orally. 1. Bacterial conjunctivitis and blephritis.
Erythromycin is also available as ophthalmic Macrolides can be used to treat conjunctivitis
ointment. Macrolides are highly liposoluble and, caused by bacteria sensitive to them. Chronic
therefore, are well absorbed through conjunctiva or recurrent conjunctivitis may be treated
and cornea. They can also be administered with erythromycin ointment 4 times a day
intravenously. Orally administered erythromycin for 7 to 10 days, more useful as a nocturnal
is inactivated by gastric acid and thus given agent. They are also indicated in the treatment
as an enteric coated formulation. Esters of of adult inclusion conjunctivitis (AIC) and
erythromycin such as stearate or estolate are neonatal inclusion conjunctivitis (NIC). For
resistant to inactivation. Clarithromycin is less AIC, erythromycin 250 mg is administered
susceptible to acid but undergoes extensive first orally 4 times a day for 21 days and for NIC,
pass hepatic metabolism.47 erythromycin 50 mg/kg/day divided in 4 daily
After systemic administration, macrolides doses for 14 days. Erythromycin ophthalmic
penetrate well into all tissues including ocular ointment may be applied to newborn eyes
within 1 hour of delivery for prophylaxis therapy with azithromycin and clarithromycin
against NIC. has been less than with erythromycin.51 Table
2. Trachoma. Macrolides are used in the treatment 8.7 summarizes the key differences between
of trachoma. In children, azithromycin 20 mg/ erythromycin, clarithromycin and azithromycin.
kg orally may be given as a single dose due to
its significant postantibiotic effect. 50 Contraindications
Adverse Effects Patients with severe liver disease should not be
given macrolides due to increased risk of toxicity
The most frequent side-effects of oral erythromycin and altered handling. Macrolides should not be
are gastrointestinal and are dose-related. They given to patients with previous history of an
include nausea, vomiting, abdominal pain, allergic reaction to them.
diarrhea and anorexia. Onset of the symptoms
of pseudomembranous colitis may occur during
or after antibacterial treatment. Symptoms of Interactions
hepatitis, hepatic dysfunction and/or abnormal Macrolides inhibit cytochrome P450 and can
liver function tests may occur. Erythromycin increase plasma concentration and toxic effects of
has been associated with QT prolongation and some drugs. The degree of cytochrome inhibitory
ventricular arrhythmias, including ventricular potency of macrolides is as follows: Erythromycin
tachycardia and torsades de pointes. Allergic > Clarithromycine > Josamycin = Roxithromycin
reactions with rash and eosinophilia can occur > Midecamycin > Azithromycin > Spiramycin.
rarely. A less well-known but nonetheless Therefore, azithromycin is unlikely to interact with
significant adverse reaction to erythromycin, drugs metabolized via the hepatic cytochrome P450
especially after intravenous administration, is enzyme system, and few interactions have been
ototoxicity, which manifests as tinnitus and/or reported clinically.52 Earlier case reports on sudden
deafness. death prompted a study on a large cohort that
Azithromycin and clarithromycin have fewer confirmed a link between erythromycin, ventricular
gastrointestinal side-effects than erythromycin. tachycardia and sudden cardiac death in patients
The most frequent side-effects are diarrhea, also taking drugs that prolong the metabolism
nausea, abnormal taste, dyspepsia, abdominal of erythromycin (like verapamil or diltiazem) by
discomfort, and headache. Most of these events are interfering with CYP3A4.53 Hence, erythromycin
mild or moderate in severity. Overall, in clinical should not be administered in patients using these
trials, the rate of premature discontinuation of drugs, or drugs that also prolong the QT time. Other
Table 8.7 Key differences among macrolides
1. Azithromycin and clarithromycin have improved tolerability and fewer gastrointestinal side-effects than
erythromycin.
2. Azithromycin is considered to have little potential for interactions than erythromycin and clarithromycin.
3. Azithromycin and clarithromycin have improved pharmacokinetic properties—better bioavailability, better

tissue penetration, prolonged half-lives.
4. Clarithromycin and azithromycin have advantages over erythromycin in dosing regimen.
5. The Gram-positive activity of clarithromycin is superior to that of erythromycin and azithromycin.
6. Azithromycin offers increased Gram-negative coverage compared to erythromycin and clarithromycin.

examples include terfenadine, astemizole, cisapride Table 8.8 Classification of aminoglycosides
(withdrawn in many countries for prolonging the
Generation Drugs
QT time) and pimozide.
First generation Streptomycin
Kanamycin
Neomycin
AMINOGLYCOSIDES Framycetin
The aminoglycosides are a clinically important Second generation Gentamicin

Tobramycin
group of antibiotics that have bactericidal action. Netilmicin
The family includes streptomycin, gentamicin, Third generation Amikacin
tobramycin, kanamycin, amikacin and netilmicin. Sisomicin
Aminoglycosides that are derived from bacteria
of the Streptomyces genus are named with
the suffix-mycin, whereas those derived from is an active one, requiring energy and oxygen.
Micromonospora are named with the suffix Uptake specifically into Gram-positive organisms
-micin. is enhanced by cell wall inhibitors such as beta
lactams. Once in the cell, aminoglycosides inhibit
The aminoglycosides consist of a centrally
the protein synthesis in the following ways:
positioned hexose nucleus, which is linked by
1. Aminoglycosides interrupt the formation of the
glycosidic bonds with 2 or more amino sugars.
essential initiation complex and instead form
The aminoglycoside families differ from each
abnormal and dysfunctional complexes.
other by having different amino sugars. Neomycin 2. Aminoglycosides induce misreading of the
and paromomycin have 3 aminosugars while code leading to incorporation of the wrong
kanamycin and gentamicin have 2 amino sugars amino acid into the peptide chain.
(Fig. 8.12). 3. Aminoglycosides prevent the monosomal
linkages, thereby, inhibit the formation of
Classification (Table 8.8) polyribosomes.54
It remains unclear how aminoglycosides
Mechanism of Action cause bacterial cell death. Inhibition of protein
Aminoglycosides inhibit bacterial protein synthesis provides inadequate explanation of
synthesis and lead to bacterial cell death. The its bactericidal effect as other protein inhibitors
uptake of aminoglycosides into the bacterial cell produce bacteriostatic effects.
Figure 8.12 Structure of aminoglycoside: streptomycin and gentamicin

Antibacterial Spectrum result of decreased intracellular concentrations

of the antibiotic.
Aminoglycoside antibiotics are primarily active Bacteria producing enzymes that can
against Gram-negative bacteria. They are the most inactivate aminoglycoside are also resistant
useful group of antimicrobials for the treatment of to aminoglycosides. Because of structural
Gram-negative infections. Aminoglycosides have differences, amikacin is not inactivated by the
no activity against anaerobic bacteria and little common enzymes that inactivate gentamicin
activity against Gram-positive bacteria. and tobramycin. Therefore, a large proportion
The first generation aminoglycosides have of the Gram-negative aerobes that are resistant
more limited spectrum compared to second and to gentamicin and tobramycin are sensitive to
third generations. They are effective against M. amikacin. In addition, with increased use of
tuberculosis and streptomycin is still the first line amikacin, a lower incidence of resistance has
drug in the treatment of tuberculosis. been observed compared with increased use of
The second generation aminoglycosides gentamicin and tobramycin.55
are effective against most aerobic Gram-
negative bacilli, especially Enterobacteriaceae
Pharmacokinetics
(E. coli, Proteus species, Klebsiella species,
Enterobacter species, Serratia species), and Topically applied aminoglycosides are primarily
nonfermentative Gram-negative bacilli (P. absorbed through conjunctiva due to their
aeruginosa, Acinetobacter species). Tobramycin hydrophilic nature. Periocular injections
is more active by one or two MIC tube dilutions (subconjunctival) provide significant ocular
than gentamicin against Pseudomonas aeruginosa tissue concentration. Aminoglycosides are poorly
whereas gentamicin is usually more active against absorbed from the gastrointestinal tract. After
Serratia. Other aerobic Gram-negative bacilli parenteral administration, aminoglycosides are
(Neisseria gonorrhoeae, Neisseria meningitidis, primarily distributed within the extracellular
Haemophilus influenzae) are susceptible but are fluid. They do not penetrate well into the aqueous
rarely treated with aminoglycosides. humor and vitreous fluid of the eye. Penetration of
Amikacin according to its chemical structure biologic membranes is poor because of the drug’s
is not inactivated by aminoglycoside-inactivating polar structure, and intracellular concentrations
enzymes and has been successfully used against are usually low, with the exception of the proximal
gentamicin-resistant strains. Enterococcal renal tubule.
infections may be treated with a combination of Aminoglycosides are primarily eliminated
aminoglycosides with penicillin, ampicillin, or unchanged by the kidney through glomerular
vancomycin. filtration. This route accounts for elimination of
approximately 85 to 95% of the dose administered
Bacterial Resistance resulting in a prolonged plasma half-life in
patients with impaired renal function. The half-
Bacterial resistance to aminoglycosides occurs life of aminoglycosides in the renal cortex is
when a bacteria undergoes structural changes approximately 100 hours, so repetitive dosing
such as the bacterial cell loses its permeability may result in renal accumulation and toxicity.
to aminoglycosides or there is a conformational
change in the structure of the receptors at the
Concentration-dependent Effect
ribosomal subunit and aminoglycosides can no
longer bind to them. P. aeruginosa may show Aminoglycosides have concentration-dependent
adaptive resistance to aminoglycosides. This bactericidal effect. The rate and extent of bacterial
occurs when formerly susceptible populations killing increases with increase in concentration.
become less susceptible to the antibiotic as a It is suggested that the optimum antibacterial
effect is observed at serum concentration to Types of Ocular Infection Suitable for
bacterial MIC ratio of > 10:1. The postantibiotic Treatment by Aminoglycosides
effect of aminoglycosides may not increase with
concentration and Gram-negative bacteria may 1. Acute conjunctivitis, blepharitis and blepharo
show reducing postantibiotic effect over time with conjunctivitis.
multiple doses of aminoglycoside. 2. Bacterial keratitis and corneal ulceration.
3. Dacryocystitis and dacryoadenitis.
Administration and Dosage 4. Bacterial endophthalmitis. Amikacin is the
aminoglycoside of choice for the treatment
The commercially available topical ocular of Gram-negative bacterial endophthalmitis,
aminoglycosides include gentamicin, neomycin, because it is thought to be less toxic to
framycetin and tobramycin. The fortified intraocular structures than gentamicin and
1.5% preparation, available from special order tobramycin.
manufacturers, is used in combination with a 5. Prophylaxis of post-operative infections.
cephalosporin for the treatment of bacterial Tobramicin and neomycin are used for
keratitis. Gentamicin causes corneal toxicity prophylaxis against infections following
at this strength. Neomycin is rarely used alone ocular surgery. Tobramycin is said to be
as an antibacterial agent but is widely used in less allergenic than neomycin. In addition,
combination with topical corticosteroids in neomycin use is limited by the side-effect of
preparations such as Betnesol-N and Maxitrol. contact dermatitis, which is said to occur in up
Framycetin, which has a similar antibacterial to 4% of patients.
spectrum to neomycin, previously available as
a single agent in eyedrop and ointment form, Adverse Effects and Interactions
is now only available with gramicidin and
dexamethasone as Sofradex eye/ear drops for The toxicities of aminoglycosides include
the short-term treatment of steroid responsive nephrotoxicity, ototoxicity (vestibular and
conditions of the eye when prophylactic antibiotic auditory) and, rarely, neuromuscular blockade
treatment is also required. Tobramycin, like and hypersensitivity reactions.
framycetin, is only available as a combination Ototoxicity is usually irreversible. Originally,
product. Tobradex contains tobramycin and ototoxicity was believed to result from transiently
dexamethasone. Gentamicin is also administered high peak serum concentrations, resulting in
subconjunctivally and intravitreally. a high concentration of drug in the inner ear.
Recent studies in animal models have indicated
that aminoglycoside accumulation in the ear is
Therapeutic Uses dose-dependent but saturable. Once a threshold
Gentamicin and tobramycin (in fortified form) concentration of the antibiotic has been reached,
has been a “go to” agent for the treatment of increasing the drug concentration results in no
Gram-negative ocular infections, especially further uptake.
Pseudomonas aeruginosa. Gentamicin is the Nephrotoxicity, which is usually reversible,
aminoglycoside used most often because of its low is mostly associated with systemic treatment by
cost and reliable activity against Gram-negative aminoglycosides, though the case of acute renal
aerobes. However, local resistance patterns failure after topical fortified gentamicin has also
should influence the choice of therapy. In general, been repoted.55 Nephrotoxicity results from renal
gentamicin, tobramycin and amikacin are used cortical accumulation resulting in tubular cell
in similar circumstances, often interchangeably. degeneration and sloughing. Examination of
urine sediment may reveal dark-brown, fine or
granulated casts consistent with acute tubular
necrosis but not specific for aminoglycoside
renal toxicity. Monitoring of serum creatinine
level may indicate renal toxicity, although
it is more reflective of glomerular damage.
Certain medications such as loop diuretics, ACE Figure 8.13 Structure of sulfacetamide
inhibitors, amphotericin and other nephrotoxic acid (PABA), a factor required by bacteria for
medications may increase the risk of renal toxicity folic acid synthesis (Fig. 8.14). Sulfonamides
with aminoglycoside use. are competitive antagonists of PABA and inhibit
the bacterial enzyme, dihydropteroate synthase
Contraindications that is responsible for incorporation of PABA
Aminoglycosides are contraindicated for use into dihydrofolic acid, the precursor of folic
in patients with allergic reactions to amin acid. Thus sulfonamides inhibit the biosynthesis
oglycosides, myasthenia gravis, severe cardi of folic acid, which is essential for the growth of
ovascular pathology, severe renal diseases susceptible organisms as folic acids is essential
and uremia, disorders of cerebral circulation, for the synthesis of purine nucleotides for DNA
pregnancy and breastfeeding. and RNA.
Only organisms that have to synthesize their
own folic acid are inhibited by sulfonamides.
SULfONAMIDES Animal cells and bacteria that are capable of
utilizing folic acid precursors or preformed
Sulfonamides were the first antibacterial agents folic acid are not affected by these drugs.
used systemically for the treatment of bacterial The antibacterial activity of the sulfonamides
infections. They are synthetic derivatives of para- decreases in the presence of blood or purulent
aminobenzene sulfonamide (sulfanilamide). They exudates, which contain PABA.
are widely used antibacterial agents because they Sulfonamides are bacteriostatic drugs and final
are relatively cheaper than other anti-bacterial eradication of infection depends also on cellular
agents. They are rarely used alone today. Often, and humoral defense mechanisms of the host.
they are combined with trimethoprim, which is
not chemically related but is considered here
Trimethoprim (TMP)
because their modes of action are complementary.
The sulfonamide that is most commonly used to Trimethoprim is a potent inhibitor of the bacterial
treat ocular infection is sulfacetamide (Fig. 8.13). enzyme dihydrofolate reductase and interferes
Table 8.9 Classification of sulfonamides
Classification
Class Drugs
Sulfonamides are classified on the basis of
Absorbed and Sulfisoxazole
rapidity of their absorption and excretion (Table excreted rapidly Sulfamethoxazole
8.9). Sulfadiazine
Well-absorbed and Sulfadoxine
Mechanism of Action excreted slowly (long-
acting)
Sulfonamides Poorly absorbed Sulfasalazine
Sulfonamides are derived from sulfanilamide, Topically used Sulfacetamide

Silver sulfadiazine
which is similar in structure to para-aminobenzoic
competitively with the conversion of dihydrofolic Escherichia coli, Shigella species, Klebsiella
acid to tetrahydrofolic acid (Fig. 8.14). It is a species However, acquired bacterial resistance
bacteriostatic drug. has now diminished the clinical usefulness of
sulfonamides.
Cotrimoxazole
Cotrimoxazole is a combination of a sulfonamide
Pharmacokinetics
(sulfamethoxazole) and trimethoprim. Combined All orally administered sulfonamides are rapidly
administration of both trimethoprim and absorbed and are distributed throughout the
sulfonamides exerts synergistic antimicrobial body. They are metabolized in the liver by
activity leading to bactericidal effect.The glucuronidation. The free drug and its metabolites
synergistic effect is because of sequential blockade are excreted in the urine. Sulfonamides compete for
of two steps in the same metabolic pathway bilirubin-binding sites on albumin. Sulfacetamide
of folic acid synthesis. The regular strength sodium is suitable for ophthalmic use because it
cotrimoxazole tablets contain trimethoprim and is freely soluble in water and less alkaline and,
sulfamethoxazole in the ratio of 1:5 (80 mg of therefore, less irritating to the conjunctiva than
trimethoprim and 400 mg of sulfamethoxazole). other sulfonamides.
This proportion provides an ideal blood ratio of Trimethoprim is well absorbed and excreted
1:20 and provides synergy. by the kidneys.
Antibacterial Spectrum Administration and Dosage

Initially sulfonamides possessed a wide range Sulfonamides generally are used in the oral
of antimicrobial activity against both Gram- form, though parenteral preparations are also
positive and Gram-negative bacteria such available. Sulfacetamide sodium is a white,
as Staphylococcus aureus, Streptococcus odorless, crystalline powder with a bitter taste
pneumoniae, Streptococcus pyogenes, Neisseria and is freely soluble in water and sparingly
meningitidis, Haemophilus influenzae, soluble in alcohol. Commercially available 30%
ophthalmic solutions of sulfacetamide sodium
have a pH of 6.8–7.5, whereas, the solutions of
other sulfonamides are highly alkaline.
Therapeutic Uses
Treatment of conjunctivitis, corneal ulcers, and
other superficial infections of the eye caused by
susceptible Staphylococcus aureus, Streptococcus
pneumoniae, Streptococcs viridans, Haemophilus
influenzae, Enterobacter, Escherichia coli, and
Klebsiella.
Adverse Effects
Topical
Figure 8.14 Biosynthetic pathway of tetrahydrofolic The most frequently reported adverse effects
acid with PABA and sites of action of sulfonamides and following topical application of sulfacetamide
trimethoprim sodium ophthalmic preparations are local
irritation, stinging, and burning. Conjunctivitis, Interactions
conjunctival hyperemia, and secondary infections
have been reported less frequently. Gentamicin sulfate antagonizes the action
Topical application of sulfonamides may of sulfacetamide sodium, so concomitant
produce sensitization and subsequent systemic administration should be avoided.
use should be avoided. Similarly for patients
sensitized following systemic use, topical BACITRACIN
application should be avoided. Stevens-Johnson
syndrome following use of sulfacetamide sodium Bacitracin, an antibiotic substance derived from
ophthalmic ointment has been reported in a patient the cultures of Bacillus subtilis, has antibacterial
with history of bullous lesions with systemic action in vitro against a variety of Gram-positive
sulfonamide therapy. Local hypersensitivity and a few Gram-negative organisms. It is not
that progressed to a fatal syndrome resembling used parenterally because it can cause renal
systemic lupus erythematosus has also been necrosis with systemic use. It is mainly reserved
reported. for topical use.
Systemic Mechanism of Action

Systemic adverse effects associated with sulfon
Bacitracin inhibits synthesis of cell wall by
amides include folate deficiency, hyperkalemia
inhibiting the precursor peptidoglycan from
(trimethoprim can decrease renal tubular potassium
migrating from the cytoplasm through the cell
excretion) and renal insufficiency. Nausea,
wall for incorporation into the peptidoglycan
vomiting, and rash are more common. Patients
layer.
with AIDS have a high incidence of adverse effects,
especially fever, rash and neutropenia.
Folate deficiency may result in macrocytic Antibacterial Spectrum
anemia. Use of folinic acid can prevent or treat Bacitracin has a narrow antibacterial spectrum.
macrocytic anemia, leukopenia and throm Gram-positive bacteria such as Staphylococcus
bocytopenia, which sometimes occur with species and Streptococcus species are susceptible.
prolonged cotrimoxazole use. Gram-negative bacteria are mostly resistant,
Rarely, severe hepatic necrosis occurs. The except Neisseria species.
drug may also cause a syndrome resembling
aseptic meningitis. Like other broad spectrum Pharmacokinetics
antibiotics, the use of sulfonamides may result
in the overgrowth of non-susceptible organisms It is not absorbed after topical application or oral
including fungi (superinfection). administration, although completely absorbed
following intramuscular injection. It is slowly
Contraindications excreted by glomerular filtration and appears in
urine within 24 hours.
The possibility of adverse reactions associated
with systemic use of sulfonamides should Administration and Dosage
be considered in patients receiving topical
sulfonamides. Sulfonamides are contraindicated Bacitracin is available as a single-agent prep
in patients who have previously exhibited aration and is also present as a component in
hypersensitivity to sulfonamides or other a fixed-combination preparation. The topical,
ingredients in the formulations. preparation of bacitracin is in the form of ointment
as the drug is not stable in solution. However, Interactions
more commonly a combination of neomycin,
polymyxin and bacitracin ointment is used to Like other cell wall inhibitors, bacteriostatic drugs
treat superficial infections of conjunctiva, eyelids could antagonize bacitracin. There is no known
and cornea. specific interaction with other drugs.
Therapeutic Uses POLYMYXIN B

Bacitracin is never used as a systemic agent Polymyxins are a group of antibiotics derived
because it causes serious nephrotoxicity. It is from Bacillus polymyxa.
usually used in combination with polymixin B
and neomycin, both of which have antibacterial
Mechanism of Action
activity against Gram-negative bacteria, thereby,
complementing the antibacterial activity of Polymyxin B is a cell membrane inhibitor and is
bacitracin, which has activity against Gram- bactericidal. It interferes with the phospholipids
positive bacteria. Hence, the antibacterial in the cell membrane. This disrupts the membrane
spectrum of the preparation is enhanced and integrity and the bacterial cell loses its selective
the preparation is effective against common permeability leading to bacterial cell lysis and
pathogens causing ocular surface infections. death.
Types of Ocular Infection Suitable for Antibacterial Spectrum

Treatment by Bacitracin Polymixin B is effective against Gram-negative
bacteria including E.coli, Klebsiella species,
1. Acute and chronic conjunctivitis and blep
Salmonella species, Shigella species, Pasteurella,
haritis caused by S. aureus and other
Acinetobacter and Pseudomonas aeruginosa.
susceptible bacteria.
Proteus and Serratia species are intrinsically
2. Keratitis and corneal ulcers caused by Gram-
resistant.
positive flora.
Pharmacokinetics
Adverse Effects
Polymixin B has no oral absorption and it is
Topical poorly absorbed from mucous membranes. It is
Hypersensitivity reactions, though rare, can excreted by kidney.
manifest as contact dermatitis.
Therapeutic Uses
Systemic Polymixin B is not used systemically as it causes
The most serious systemic adverse effect is neurotoxicity and nephrotoxicity. Topically, it
nephrotoxicity. is used in combined preparations with other
anti-infectives such as bacitracin (see section on
Contraindications bacitracin). A combination of polymixin B and
trimethoprim is also complementary because
Bacitracin should be avoided in patients with although trimethoprim is active against many
known sensitivity toward it and those with Gram-positive and Gram-negative bacteria
impaired renal function. but it is not active against Pseudomonas
aeruginosa, which is susceptible to polymixin correlation with molecular structure. Antimicrob
B. Trimethoprim/polymixin B ophthalmic Agents Chemother. 1995;39(6):1211–33.
preparation is available as ointment and solution. 6. Barry G Hall, Miriam Barlow. Revised Ambler
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injections. Chemother. 2005;55(6):1050–1.
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Interaction 9. Kaplan EL, Berrios X, Speth J, Siefferman T,
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ChapteR 9
Antiviral Drugs
OVERVIEW herpes simplex virus (HSV) from that of

varicella zoster virus (VZV).
Ocular diseases due to viral infection are one of Direct and indirect immunofluorescence,
the most challenging in terms of diagnosis and indirect immunoperoxidase assays are rapid,
treatment. Firstly, viruses are obligate intracellular specific and sensitive test systems that can be
parasites that are too small to be observed with used in the diagnosis of HSV, VZV keratitis,
light microscope. Secondly, virus particles have and adenoviral keratoconjunctivitis. Indirect
rugged molecular machinery that has evolved immunoperoxidase (IP) assay is preferred as
over time to ensure efficient transfer of genetic it can be applied on paraffin embedded tissue,
material between cells in stepwise manner allows preparation of permanent records and
(attachment, penetration, and initiation of a new needs ordinary light microscope for visualization.
replication cycle) and mechanisms to safeguard In contrast, the indirect immunofluorescence
encoded information sufficient to ensure their is usually conducted on frozen tissue sections,
own continued propagation and escape. Thirdly, quenching leads to fading of records and requires
the molecular organization of viruses is still sophisticated and expensive fluorescence
incompletely understood as it is highly nascent microscope for visualization.1,2
and keeps modifying as per environmental Conventional practice of viral isolation using
conditions. Fourthly, the preponderance of variety cell lines such as HeLa, Vero, HEp 2 and MRC-
in viral machinery like polymerases, envelope/ 5 are very sensitive and useful in providing
non-envelope, double-stranded (ds) DNA/RNA/ evidence for the presence of virus in ocular
nucleic acids and regulatory proteins can lead to scrapings and samples. However, this can be
lysis or stimulation or even transformation of host time and technically demanding, as it requires
cells, making these agents difficult to read and special and expensive virology laboratory set up.
predict. Last but not the least, despite aggressive In recent advancement, merely demonstration
treatment the virus can survive as latent infection of presence of viral genetic material in clinical
making the host its long-standing carrier and samples is taken as evidence of its presence and
reactivate later in severe and fatal form. the need for isolation has been done away with. 1,2
Detection of cell-associated viral antigen for The current bouquet of antiviral agents is
diagnosing infection using conventional staining effective and has been in ophthalmic use for
techniques such as Papanicolaou and Giemsa long, but is fraught with some limitations.
stain is although, rapid and inexpensive, but Most antiviral agents that are available to treat
self-limiting owing to non-specificity and low dsDNA viruses inhibit the same target, the
sensitivity. For example, these stains cannot viral DNA polymerase. Hence, with increasing
differentiate the intra-nuclear inclusions of reports of the development of resistance to these
drugs, new antiviral agents are urgently needed the treatment of DNA virus infections including
for management of HSV, cytomegalovirus and adenovirus, smallpox, molluscum contagiosum,
Hepatitis B virus (HBV) infections. Further, and BK virus.
there is paucity of drugs that are available for Following is the detailed discussion of antiviral
drugs that are currently in ophthalmic use (Table 9.1).
Table 9.1 Antiviral drugs

Drug Mechanism of action Antiviral activity Therapeutic uses
Idoxuridine (IDU) Replaces thymidine in viral DNA, HSV-1- and -2 Superficial herpes simplex
inhibits viral DNA polymerase keratitis
and interferes with other cellular
enzymes
Trifluridine Same as IDU HSV-1 and Primary and recurrent herpes
-2; vaccinia, simplex keratoconjunctivitis,
adenovirus and dendritic and geographic
cytomegalovirus ulcers
Vidarabine Inhibits viral DNA polymerase, HSV-1 and -2, Herpes simplex
competes with adenosine vaccinia and VZV keratoconjunctivitis and iritis,
triphosphate for incorporation herpetic ulcers
into viral DNA
Acyclovir Active form inactivates viral HSV-1 and-2 Herpes simplex epithelial
(Valacyclovir DNA polymerase. It replaces keratitis, stromal keratitis,
is a prodrug of guanosine in viral DNA dendritic herpetic ulcer, iritis
acyclovir) and acute retinal necrosis;
prophylaxis in patients
undergoing keratroplasty
for active herpes
simplex keratitis and in
immunosuppressed patients;
herpes zoster and varicella
infections
Famciclovir Inhibits DNA polymerase HSV-1, HSV-2 and Herpes simplex infections,
(A prodrug of VZV zoster ophthalmicus, acute
penciclovir) retinal necrosis especially in
cases of acyclovir resistance
Ganciclovir Competes with deoxyguanosine Cytomegalovirus, Cytomegalovirus retinitis,
(Valganciclovir is triphosphate for incorporation HSV-1 and 2, of severe cytomegalovirus
an oral prodrug of into the viral DNA, inhibits viral Epstein Barr virus infections such as respiratory,
ganciclovir) DNA polymerase and VZV gastrointestinal and
disseminated infections
Cidofovir Inactivates viral DNA polymerase Cytomegalovirus Cytomegalovirus retinitis
including strains
resistant to
ganciclovir, HSV-
1 and -2, VZV,
Epstein Barr virus,
vaccinia and several
adenoviruses
Foscarnet Selective and noncompetitive Cytomegalovirus, Cytomegalovirus retinitis in
inhibitor of viral DNA HSV-1 and -2, VZV HIV-infected patients, herpes
polymerases and reverse and Epstien Barr simplex and zoster infections
transcriptase virus, HIV resistant to acyclovir in HIV
patients
Antiviral Drugs 137
IDOXURIDINE (IDU) epithelial infections and not for stromal keratitis

or iritis as it does not penetrate the cornea
IDU is the oldest antiviral drug that was well. Use of IDU has diminished now due to
used topically in ophthalmic practice. It was availability of newer antiviral agents.
synthesized in 1959 as an anticancer drug but was
later found to have antiviral properties. Dosage and Administration
IDU for topical application is available as 0.1%
Mechanism of Action
drops and 0.5% ointment. In the treatment of
IDU is a thymidine analogue. The only difference herpetic keratitis, drops are instilled every 1–2
in its structure from thymidine is that it consists hour daily and ointment at bed time for 14 days.
of iodine at carbon 5 instead of methyl group
and, therefore, its configuration resembles that Adverse Effects
of thymidine. Due to resemblance in structure,
it replaces thymidine in viral DNA leading to Systemic use of IDU is minimally effective
production of faulty DNA. IDU is phosphorylated and highly toxic. It is teratogenic, mutagenic
by viral and cellular kinases. IDU triphosphate and potentially carcinogenic and, therefore, is
inhibits viral DNA polymerase and, therefore, not used systemically. Topical administration
in eye may cause punctate epithelial keratitis,
prevents viral replication. Additionally, IDU
conjunctivitis, punctal stenosis, contact dermatitis
triphosphate terminates viral replication also by
and keratinization of lid margins. It interferes with
interfering with other cellular enzymes such as
stromal healing and may cause toxic epithelial
thymidine kinase, deoxycytidine monophosphate
changes.
deaminase and cytidine diphosphate reductase.
Similar effects in host cells lead to toxic effects
of IDU. TRIFLURIDINE
Pharmacokinetics Trifluridine is a thymidine analogue. Its structure is

similar to that of IDU except that it has 3 fluorine
Topically applied IDU penetrates the intact cornea atoms attached to methyl radical replacing the
poorly. It penetrates the cornea well only if the iodine.
epithelium is damaged. Systemic absorption after
ocular administration is unlikely. It is rapidly Mechanism of action
metabolized by deaminases or nucleotidases.
Although exact mechanism of antiviral effects of
trifluridine is not known, it seems to act in the same
Antiviral Activity
way as IDU. It inhibits several steps in the synthesis
IDU is effective against HSV-1- and -2. Modific of viral DNA. It is initially phosphorylated to
ation of thymidine kinase gene results in trifluridine monophosphate, which is a potent
emergence of resistance to IDU. IDU-resistant inhibitor of thymidylate synthetase. It is further
strains of HSV show cross-resistance to acyclovir phosphorylated to its triphosphate compound,
and intermediate resistance to trifluridine but which competes with thymidine triphosphate for
remain sensitive to vidarabine and ganciclovir. 3 incorporation into the viral DNA.
Therapeutic Uses Pharmacokinetics

IDU is used topically for the treatment of herpes In contrast to IDU, trifluridine penetrates
simplex keratitis. It is effective only for superficial the intact cornea well and in the presence of
damaged cornea it achieves even higher aqueous It is too toxic for systemic use. Like IDU,
humor levels. Systemic absorption after topical it has teratogenic, mutagenic and carcinogenic
application is negligible. properties.
Antiviral Activity VIDARABINE

It is effective against HSV-1 and -2. It also has
activity against vaccinia and some adenoviruses.4 Vidarabine is a guanosine analogue. It is obtained
Its activity against human cytomegalovirus has from fermentation cultures of Streptomyces
also been reported.5 antibioticus. It is also known as adenine
Resistance to trifluridine is rare and if it arabinoside or Ara-A. Vidarabine was the first
occurs, the mechanism is similar to that of IDU. antiviral drug that became generally available for
parenteral treatment of severe herpes infection
in human. Besides its antiviral effects, it also
Therapeutic Uses possesses antineoplastic properties.
Trifluridine is effective in the treatment of primary
and recurrent herpes simplex keratoconjunctivitis. Mechanism of Action
In patients with dendritic ulcer, its efficacy is
comparable to vidarabine and IDU. It may also Vidarabine has high affinity for viral encoded
be effective in patients with geographic ulcers. thymidine kinase, which converts it into vidarabine
Average healing time is 6–7 days. Its efficacy is monophosphate. Further phosphorylation by
similar to topical acyclovir both in terms of healing viral and cellular kinases leads to formation
rate and time for healing. It is especially useful for of its triphosphate form. The triphosphate is
the treatment of ulcers not responding to IDU or both an inhibitor and substrate for viral DNA
vidarabine and in patients intolerant to IDU.6 polymerase. Vidarabine triphosphate competes
with adenosine triphosphate for incorporation into
Dosage and Administration viral DNA leading to formation of faulty DNA and
termination of viral replication.
Trifluridine 1% solution is applied every 2 hours
while awake to a maximum of 9 drops/day until
cornea is re-epithelialized. Subsequently, dose is Pharmacokinetics
tapered to every 4 hours with a maximum of 5 Topically applied vidarabine penetrates the intact
drops/day for 7 days. Total duration of treatment cornea poorly. Systemic absorption after topical
should not be more than 21 days. In cases administration is negligible.
showing no response after 7 days of treatment or Following intravenous administration, it
incomplete epithelialization after 14 days, changeundergoes rapid deamination by adenosine
in therapy is indicated. deaminase to form arabinosyl hypoxanthine,
which has much less activity than vidarabine.
Adverse Effects To increase the antiviral activity of vidarabine it
Topically applied trifluridine is well tolerated. has been combined with inhibitors of deaminase.
Cross-toxicity with IDU or vidarabine is rare. The combination, though increases the antiviral
Ocular adverse effects of topical application effects, the toxicity also increases.
include transient burning and stinging, punctate
epithelial keratitis, conjunctival hyperemia and Antiviral Activity
chemosis, keratitis sicca, punctual stenosis,
contact dermatitis, palpebral edema and poor Vidarabine is effective against HSV-1 and -2,
stromal wound healing. Long-term use can cause vaccinia and VZV. It has poor activity against
conjunctival scarring. RNA viruses.
Antiviral Drugs 139
Resistance to vidarabine may emerge due which undergoes further phosphorylation by host
to development of mutations in viral DNA cellular enzymes to diphosphate and triphosphate.
polymerase gene. Acyclovir triphosphate is the active forms of the
drug that inactivates viral DNA polymerase. It
Therapeutic Uses also gets incorporated in viral DNA causing its
termination.
Vidarabine ointment 3% has been shown to
be effective in the treatment of herpes simplex
keratoconjunctivitis and iritis. Its efficacy for Pharmacokinetics
promoting re-epithelialization is comparable After oral administration, bioavailability of
to IDU, however, it is less toxic and even acyclovir is 20%. However, oral valacyclovir
causes healing of IDU-resistant lesions. Topical is rapidly metabolized in intestine and liver
vidarabine is also comparable to topical trifluridine to acyclovir and bioavailability of acyclovir
and acyclovir in healing corneal herpetic lesions. following oral dose of valacyclovir increases by
Systemic vidarabine, although effective in the 3–5 times. The plasma protein binding ranges
treatment of varicella and zoster ophthalmicus, from 9–33%. It is adequately distributed in
is not a preferred choice. tissues. The intracellular half-life of acyclovir is
0.7 and 1 hours in HSV-1 and -2 infected cells,
Adverse Effects respectively, and 0.8 hours in VZV infected
cells as detected from in vitro experiments.7 It
The toxicity of both, the topical and systemic,
undergoes minimal metabolism and is primarily
vidarabine is negligible. Systemic administration
excreted unchanged in urine after glomerular
of vidarabine requires large volume of fluid due
filtration and tubular secretion. The half-life of
to its relative insolubility and, therefore, may
acyclovir is significantly affected by change in
cause cardiovascular and renal homeostatic
renal function and, therefore, dose adjustment
consequences. It also has teratogenic, mutagenic
is required in patients with impaired renal
and carcinogenic potential. Therefore, systemic
function. Elderly may require a lower dose due
use of vidarabine is limited to life-threatening
to age-related changes in renal function.8 Regular
infections not responsive to other drugs.
intravenous administration of 5 mg/kg, 3 times a
day provides the vitreous levels that are in excess
VALACYCLOVIR AND ACYCLOVIR of minimum inhibitory concentration for HSV-1-
and -2, VZV and Epstein Barr virus.
Acyclovir is a synthetic guanosine analogue with
selective anti-herpes activity. It was discovered in Antiviral activity
1974 and was subjected to clinical trials in 1977.
Topical preparation of acyclovir first became Acyclovir is known as a selective anti-herpes
available for use in 1982. Valacyclovir, a prodrug, agent as it is highly active against HSV-1 and
is L -valyl ester of acyclovir and was synthesized -2, less effective against VZV and even less
to enhance oral bioavailability of acyclovir. against Epstein Barr virus and cytomegalovirus.
Uninfected and normal cells remain unaffected.
Mechanism of Action Chronic and intermittent administration of
acyclovir, especially in AIDS patients, may
It is concentrated in viral infected cells and has result in development of resistance and failure of
high affinity for viral-induced thymidine kinase. therapy. Development of resistance often results
Inside the infected cells, viral thymidine kinase from quantitative or qualitative changes in virus-
converts acyclovir to acyclovir monophosphate, induced thymidine kinase or DNA polymerase.
Therapeutic Uses excimer laser keratectomy or laser-assisted in-

situ keratomileusis (LASIK).15,16 Valacyclovir as
Acyclovir is used in the treatment of epithelial a sole agent has been shown to provide complete
keratitis, stromal keratitis, dendritic herpetic resolution of retinitis.17
ulcer, iritis and acute retinal necrosis caused by
herpes simplex. Oral administration of acyclovir
causes significantly faster healing of dendritic Dosage and Administration
herpetic corneal ulcer.9 Herpetic eye disease study
group examined the role of long-term acyclovir Acyclovir is available as 3% ointment for topical
treatment in prevention of recurrent ocular herpes application. For herpes simplex keratitis, it
in immunocompetent patients.10 It was observed is used 5 times a day for 2 weeks and is then
that cumulative probability of recurrence of any gradually tapered to twice a day. Acyclovir for
type of ocular HSV disease during the 12 month oral administration is available as 200–800 mg
treatment period was 19% in the acyclovir-treated tablets and is administered in a total daily dose
group compared to 32% in the placebo group. of 1 gram. In immunosuppressed patients, it is
Among patients with stromal keratitis, the most administered at a dose of 5–10 mg/kg or 500 mg/m .
2
severe form of the disease, acyclovir reduced the Acyclovir is administered at a dose of 5 mg/kg
recurrence rate to 14%. Recurrence of nonocular body weight 8 hourly for 5–10 days intravenously.
herpes was also reduced. Success rate for healing of Acyclovir for injection is available in 20 and
corneal ulcers with acyclovir is comparable to IDU, 40 mL vials containing 25 mg/mL of acyclovir.
trifluridine and adenine arabinoside.11-13 Acyclovir Intravitreal acyclovir 0.5 µg/100 µL has been
is used for prophylaxis in patients undergoing used in the treatment of acute retinal necrosis.
keratroplasty for active herpes simplex keratitis For the treatment of zoster, oral valacyclovir is
and in immunosuppressed patients such as those administered 1 g thrice daily for 7 days.
with AIDS, blood dyscrasias or the organ transplant
recipients. It is also used for the treatment of Adverse Effects
herpes zoster and varicella infections, however, Topically applied acyclovir ointment is well
the dose required are as high as 800 mg 5 times a tolerated. The most common adverse effects
day. It is recommended that for zoster infection, include superficial punctate keratopathy and
acyclovir should be initiated within first 72 hours burning or stinging on application of the
for better outcome. Oral acyclovir also reduces ointment. Other adverse effects are conjunctivitis
the incidence and duration of zoster-associated and pain in the treated eye.18 Systemic acyclovir
postherpetic neuralgia. For the treatment of acute
can cause gastrointestinal disturbances, anorexia,
retinal necrosis, systemic acyclovir is the treatment
dizziness, rash, edema and lymphadenopathy.
of choice. However, it takes about 2 days before
Rapid intravenous injection can cause renal
the disease progression can be prevented. Recent
dysfunction. Other adverse effects include
experiments in rabbit have shown that intravitreal
sweating, emesis, hypotension and neurological
acyclovir can be of use to provide coverage during
manifestations. Valacyclovir is not used in
initial few days of therapy and 1 mg dose was
immunosuppressed as it can cause thrombotic
found to be safe and well tolerated.14
thrombocytopenic purpura and hemolytic uremic
Valacyclovir is primarily used in the treatment
syndrome in these patients.
of herpes zoster and herpes simplex infections
in immunocompetent patients and its efficacy is
comparable to oral acyclovir. It is more effective FAMCICLOVIR AND PENCICLOVIR
than acyclovir in reducing the severity of post-
herpetic neuralgia. It has been shown to inhibit Famciclovir is a potent and selective antiviral
reactivation of ocular herpes simplex after agent with activity against herpes viruses. It is
Antiviral Drugs 141
a synthetic acyclic guanine derivative and is a in these infections is similar to oral acyclovir,
prodrug of penciclovir. however, famciclovir can be administered in
more convenient dosage regimen. In the treatment
Mechanism of Action of herpes zoster ophthalmicus also, its efficacy
and safety profile is comparable to acyclovir.
Famciclovir after oral administration undergoes Oral famciclovir can also be an alternative to
rapid metabolism to penciclovir. Like acyclovir, intravenous acyclovir in the treatment of acute
penciclovir also undergoes phosphorylation to retinal necrosis especially in cases of acyclovir
monophosphate by virus-induced thymidine resistance or for patients intolerant to prolonged
kinase and subsequently to triphosphate by intravenous treatment.19
cellular kinases. Penciclovir triphosphate inhibits
DNA polymerase and, thereby viral replication.
Dosage and Administration
Pharmacokinetics Famciclovir is available for oral administration
as tablets containing 125, 250 and 500 mg of
Famciclovir is well absorbed and is converted to
famciclovir. It is administered in the dose of 500
penciclovir with bioavailability of 65–77% after
mg thrice a day in the treatment of herpes zoster
oral administration. In vitro, intracellular half-life
ophthalmicus.
of penciclovir triphosphate is up to 10–12 hours in
cells infected with HSV-1 and -2 and 9–14 hours
in VZV infected cells. Oral famciclovir results Adverse Effects
in vitreal concentrations of penciclovir that are Most common adverse effects of famciclovir
within the inhibitory range for HSV and VZV.19 include gastrointestinal disturbance, headache and
The prolonged intracellular half-life provides nausea. It can also cause rash, fatigue, paresthesia
persistent antiviral activity. Less than 20% of and dysmenorrhea.
penciclovir is plasma protein bound. Famciclovir
is primarily excreted by kidneys. In patients with
normal or mild renal impairment, dose adjustment GANCICLOVIR AND
is not required.7 VALGANCICLOVIR
Antiviral activity Ganciclovir is a synthetic acyclic guanosine
analogue, which was the first drug to be
Famciclovir is effective against herpesvirus approved for the treatment of cytomegalovirus
family, including HSV-1, HSV-2 and VZV virus. infection. Valganciclovir is an oral prodrug of
Potency and spectrum of antiviral activity is ganciclovir.
similar to acyclovir.
Resistance may develop to famciclovir and Mechanism of Action
the mechanism of resistance involves mutation
of viral thymidine kinase and DNA polymerase After oral administration valganciclovir is converted
genes. Acyclovir-resistant mutant strains that are to ganciclovir. Ganciclovir is concentrated
negative for thymidine kinase show resistance to in the virus-infected cells and undergoes
famciclovir. phosphorylation by virus-encoded kinases.
Further phosphorylation by cellular kinases leads
Therapeutic Uses to the formation of ganciclovir triphosphate, which
competes with deoxyguanosine triphosphate for
Famciclovir is effective in the treatment of incorporation into the viral DNA and produces
immunocompetent patients with herpes zoster or faulty DNA. It also inhibits viral DNA polymerase
genital herpes infection. Its therapeutic efficacy and hence inhibits viral replication.
Pharmacokinetics Dosage and Administration

The oral bioavailability of ganciclovir is poor Ganciclovir is available as capsule containing
amounting to about 5% under fasting condition. In 250 and 500 mg of the drug. For intravenous
the presence of fatty meal, bioavailability increases administration, ganciclovir sodium is available in
to 30%. Only 1–3% of the drug in circulation is vials containing 500 mg. Reconstitution in 10 mL
plasma protein bound and up to 90% of the plasma of sterile water provides a concentration of 50 mg/
ganciclovir is excreted unchanged by kidneys mL. Ganciclovir is administered intravenously by
after glomerular filtration and tubular secretion. slow injection and not as bolus or rapid injection
The half-life of intravenously administered to avoid toxicity caused by excessive plasma
ganciclovir is 2.5–3.6 hours and it is 3.1–5.5 hours levels. Intramuscular or subcutaneous injections
after oral administration. In the presence of renal may cause severe tissue irritation due to alkaline
dysfunction, half-life increases significantly. pH of the solution. Weekly intravitreal injections
of ganciclovir 2 mg in 0.05–0.1 mL are also used
Antiviral Activity for the treatment of cytomegalovirus retinitis.
Ganciclovir is also available as a non-
It is active against cytomegalovirus, HSV-1 and biodegradable intravitreal implant. This implant
-2, Epstein Barr virus and VZV. It has widely is made of ethylene-vinyl acetate copolymer
been used for the treatment of cytomegalovirus (EVA) and polyvinyl alcohol (PVA). It contains
infections. ganciclovir 4.5 mg, which is released over 6–8
Resistance to ganciclovir may develop months by passive diffusion through a small
in patients with AIDS and cytomegalovirus opening in the EVA at the base of the device.21
retinitis receiving long-term treatment as well Besides the complications associated with the
as those who have not received treatment surgical procedure of implanting the device
previously. Mechanism of resistance is attributed inside the eye, there are concerns of the risk of
to development of mutations of viral genes spread of infection to the unaffected eye and
encoding kinases and DNA polymerase. other parts of body. The biodegradable polylactide
(PLA) containing ganciclovir implants are being
Therapeutic Uses developed. Such devices can be implanted into the
vitreous from the sclerotomy site at the pars plana.
It is used both for induction and maintenance The device does not disturb the transparency of the
treatment of cytomegalovirus retinitis in patients ocular medium and releases the active ingredient
with AIDS and other immunocompromized directly into the vitreous for up to one year.
patients. It is also used for the treatment of severe
cytomegalovirus infections such as respiratory,
Adverse Effects
gastrointestinal and disseminated infections.
For induction, 5 mg/kg is administered over Adverse effects of ganciclovir include pancyto-
hours and is repeated every 12 hours for 2–3 weeks. penia, gastrointestinal symptoms and acute renal
Following induction, maintenance treatment can failure.
be given intravenously (5 mg/kg over 1 hour once
daily, 7 days a week) or orally (1000 mg thrice a
CIDOFOVIR
day with food). Ganciclovir is used for prevention
of cytomegalovirus retinitis in high risk patients. Cidofovir is a newer antiviral drug that is classified
Topical application of ganciclovir 0.15% gel as acyclic phosphonate cytosine analogue. It
is effective in herpes simplex keratitis and the belongs to the family of phosphonyl methoxyalkyl
efficacy is comparable to acyclovir ointment.20 derivative of purines and pyrimidines.
Antiviral Drugs 143
Mechanism of Action Dosage and Administration

Cidofovir is taken up by virus-infected and For cytomegalovirus retinitis, cidofovir is given
uninfected cells. It exists in monophosphate form by intravenous infusion of 5 mg/kg once weekly
and, therefore, does not require phosphorylation for 2 weeks followed by either high dose (5 mg/
by viral thymidine kinase to get activated. kg) or low dose (3 mg/kg) weekly administration.
Cellular kinases convert it into diphosphate, It can also be given intravitreally 10–20 µg every
which inactivates viral DNA polymerase with 5–6 weeks and up to 10 injections may be given.
25–50 times higher specificity than human DNA
polymerase. Adverse Effects
In the treatment of cytomegalovirus retinitis
Pharmacokinetics two most notable adverse effects, regardless
After intravenous administration, the half-life of route of administration, are hypotony and
of cidofovir is 2.4–3.2 hours. However, the nongranulomatous iritis. Topical administration
intracellular half-life of cidofovir diphosphate may cause punctal stenosis.
is more than 48 hours resulting in long lasting Nephrotoxicity is the major dose-limiting
antiviral effects. Its protein binding is less than toxicity and may occur in 50% of patients
receiving maintenance dose of 5 mg/kg once in
6% and it is eliminated in urine. It is administered
two weeks. Neutropenia may develop in 20% of
with probenecid, which delays its renal clearance.
the patients on maintenance doses.
Cidofovir in a crystalline lipid prodrug form,
octadecyloxyethyl-cyclic-cidofovir, has shown
prolonged vitreous half-life when injected FOSCARNET
intravitreally in rabbits.22
Foscarnet is a non-nucleoside antiviral drug. It is
Antiviral Activity a trisodium salt of phosphoformic acid.
Cidofovir is effective against cytomegalovirus
including strains resistant to ganciclovir. It is also Mechanism of Action
effective against HSV-1 and -2, VZV, Epstein Foscarnet does not require phosphorylation for
Barr virus, vaccinia and several adenoviruses. activation. It directly interacts with pyrophosphate
Resistance for cidofovir is associated with prior binding site of viral DNA polymerases. It is a
treatment with oral ganciclovir or intravenous selective and noncompetitive inhibitor of viral
cidofovir. Resistant strains have mutation in UL97 DNA polymerases and reverse transcriptase
and polymerase gene. at concentrations that do not affect the host
DNA polymerase. Since it does not require
Therapeutic Uses phosphorylation by virus, the strains with mutant
gene for thymidine kinase are sensitive to foscarnet.
Cidofovir, due to its high efficacy and therapeutic
margin, is currently the firstline drug for the
treatment of cytomegalovirus retinitis. It can Pharmacokinetics
be given either intravenously or intravitreally. The half-life of foscarnet is 4 hours. It is well
Cidofovir has also been found to be effective distributed in tissues and achieves 43% of plasma
in the treatment of ocular infections caused by levels in cerebrospinal fluid. It accumulates in
adenoviruses 1, 5 and 6 in rabbit.23,24 Topical bone marrow and in AIDS patients up to 20%
cidofovir 1% and 0.5% have also shown efficacy of the administered dose can accumulate in
in treating HSV-1 in rabbits and effects were bone marrow. It is metabolized and is excreted
comparable to trifluridine and acyclovir.23,25 unchanged by kidneys.
Antiviral Activity prevent nephrotoxicity. Other adverse effects

include anemia in up to 50% of patients, elevated
Foscarnet is active against all herpes viruses hepatic enzyme, headache, central nervous
including cytomegalovirus, HSV-1 and -2 and system dysfunction, gastrointestinal disturbances,
Epstien Barr virus. It is also effective against HIV. mucosal erosions, nephrogenic diabetes insipidus
Foscarnet-resistant strains of herpes simplex and neutropenia.
have recently been reported. These strains were
also resistant to acyclovir, though thymidine
References
kinase gene mutations have not been observed
in these strains. 1. Sharma S, Sreedharan A. Diagnostic procedures
in infectious keratitis. In: Nema HV, Nema N
Therapeutic Uses (eds).Diagnostic Procedures in Ophthalmology
2nd edn. Jaypee Brothers Medical Publishers (P)
The main therapeutic indication for foscarnet is Ltd., New Delhi; 2009. pp. 316–32.
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It is also used for the treatment of herpes simplex shell vial culture and the suspension-infection
and zoster infections resistant to acyclovir method for the rapid detection of HSVes. Diagn
in HIV patients. The efficacy of foscarnet is Microbiol Infect Dis. 1993;16:61–6.
comparable to ganciclovir, although foscarnet 3. Fardeau C, Langlois M, Nugier F, Asselot C,
may prolong the survival due to its anti-HIV Aymard M, Denis J. Cross-resistances to antiviral
effects. Intravitreal foscarnet for cytomegalovirus drugs of IUdR-resistant HSV-1 in rabbit keratitis
and in vitro. Cornea. 1993;12:19–24.
retinitis is not approved by FDA, however, one
4. Schaeffer HJ, Beauchamp L, de Miranda P,
study has reported that 4 out of 5 patients showed
Elion GB, Bauer DJ, Collins P. 9-(2-Hydrox
complete healing in 3 weeks when 2.4 µg/0.1 mL
yethoxymethyl) guanine activity against viruses
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human cytomegalovirus by trifluorothymidine.
Dosage and Administration Antimicrob Agents Chemother. 1983;23(1):
113–8.
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available in 250 and 500 mL bottles containing TM, Avery GS. Trifluridine: a review of its
25 mg/mL of the drug. It is given as infusion antiviral activity and therapeutic use in the topical
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with normal saline or 5% dextrose in peripheral 23(5):329–53.
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over 2 hours every day. During infusion good 1):14–26.
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complications. acyclovir after intravenous and oral administration.
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Adverse Effects 9. Hung SO, Patterson A, Clark DI, Rees PJ. Oral
acyclovir in the management of dendritic herpetic
Nephrotoxicity is the major adverse effect corneal ulceration. Br J Ophthalmol. 1984;
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Antiviral Drugs 145
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12. la Lau C, Oosterhuis JA, Versteeg J, van Rij G, for herpes simplex keratitis. Curr Eye Res. 2012;
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ChapteR 10
Antifungal Drugs
OVERVIEW very important as treatment is often a prolonged

one. Laboratory investigations to confirm fungal
Although the fungi community is a large one, infection include microscopic examination of
it is surprising but fortunate that only a few a smear or scrapping with or without the use
species are pathogenic to the eye. Some of of stains. Determining the susceptibility of the
the pathogenic fungi affecting the eye include fungus to antifungal drugs and their MIC would
Candida, Aspergillus, Fusarium , Curvularia. As aid in choosing appropriate treatment and dose.
with bacteria, fungal virulence includes factors There are some general limitations for the
that facilitate the infection and factors that affect use of antifungals, which include their adverse
the host. Ability of fungi to attach to host cells and effects, narrow antifungal spectrum, poor tissue
presence of a polysacсharide capsule to prevent penetration, drug interactions and drug resistance.
phagocytosis by macrophages facilitates fungal There are four main classes of anti-fungals:
invasion into the host cells. Fungi cause host tissue polyenes, pyrimidines, azoles and echinocandins.
damage by invoking an inflammatory reaction by The clinical efficacy of an antifungal agent
the polysaccharide capsule and through cytokines in ocular mycosis depends to a great extent
production. They also cause direct tissue damage on the concentration of the drug achieved in
through mycotoxin production. the target ocular tissue. Factors affecting the
Fungi can affect almost every structure of concentration achieved include the molecular
the eye such as cornea, conjunctiva, lens, ciliary mass, concentration of the drug, the route by
body and the uveal tract. Factors predisposing to which it has been administered, duration of
fungal infection include prolonged use of oral or contact with the target ocular tissue and the ability
topical steroids, a suppressed immune system, of the compound to penetrate the ocular tissue.
contaminated contact lenses and injury or trauma
to ocular structures. The source of infection can
be through the blood from a systemic infection POLYENES
or through direct inoculation of the fungi to the
ocular structures. Polyenes were the first effective antifungal agents
The approach to diagnose fungal infection of discovered. These compounds share a common
the eye is similar to diagnosing fungal infection molecular structure consisting of a conjugated
of the skin or any other anatomical part of the double-bond linked to mycosamine, an amino
body. Although often not diagnostic for a fungal acid sugar. Members of this group are classified
ocular infection, history and clinical examination according to the number of double-bonds present.
must be taken to decide if the ocular infection is Polyene antifungal drugs include: Natamycin,
part of a systemic one or if it is a localized ocular nystatin and amphotericin B. Nystatin was the first
infection. Confirmation of a fungal infection is polyene identified. Amphotericin B is derived from
Antifungal Drugs 147
the bacteria, Streptomyces nodosus. Amphotericin Table 10.1 Antifungal activity of polyenes
B is a broad spectrum antifungal drug and was the
Amphotericin B Nystatin Natamycin
first polyene used for systemic mycosis.
Candida species, Candida Candida
Cryptococcus species, species,
Mechanism of Action neoformans, Cryptococcus Cryptococcus
Blastomyces neoformans,
Polyenes bind to the ergosterol present in the dermatitidis, Aspergillus
fungal cell membrane and disrupt the membrane Histoplasma species,
capsulatum, Fusarium
permeability of the organism, which interferes
Aspergillus species
with the osmotic regulation of the fungal cells.1 species,
Mammalian cells contain cholesterol instead Coccidioides
of ergosterol and, therefore, they are much less species,
Sporothrix
susceptible to polyenes. The size of the polyene schenckii,
affects the molecular interaction between the drug Paracoccidioides
and fungal cell membrane ergosterol. Larger drug braziliensis
molecules such as nystatin and amphotericin B
membranes. The corneal epithelium appears to be
bind to the cell membrane and create channels
a powerful barrier to corneal penetration of the
spanning across the cell membrane and allow
polyenes. Amphotericin B was only available in
electrolyte movement, whereas small polyenes
the injectable form as oral administration produces
like natamycin alter membrane permeability by
low bioavailability. Recently special lipid
creating localized disruptions in the membrane.2 formulations became available for both oral and
The activity of polyenes is concentration intravenous use with good bioavailability, same
dependant; lower doses inhibit fungal growth spectrum of activity, better therapeutic indices
(fungistatic) and higher doses are fungicidal. and less risk of nephrotoxicity. Amphotericin B is
currently available as conventional amphotericin
Antifungal Activity B (C-AMB), liposomal amphotericin B (L-AMB),
Polyenes have variable antifungal activity. The amphotericin B colloidal dispersion (ABCD) and
antifungal spectrum of polyenes is presented in amphotericin B lipid complex (ABLC).3 Injectable
the table 10.1. Amphotericin B also has activity form of amphotericin B reaches aqueous humor
in two-thirds of plasma concentration and that
against some protozoa such as Leishmania species
covers the MICs of most fungi.4 Nystatin is also
and Naegleria fowleri.
available in liposomal formulation which is
effective in the treatment of systemic mycosis.5
Fungal Resistance Natamycin, like other polyenes is insoluble
Generally, fungi do not demonstrate significant in water. It is unstable to light and extreme
level of resistance against polyenes, however, temperatures. The ophthalmic preparation of
some isolates of Candida and Aspergillus are natamycin 5% is available in 15 mL glass bottles
resistant to nystatin and amphotericin B. The from Alcon Laboratories. It can be stored at room
most common mechanism of polyene resistance temperature or refrigerated, but may not be placed
among mutant fungi is replacement of ergosterol in freezers. Natamycin is only for topical use
with certain precursor steroids. and not systemic. It adheres to areas of corneal
ulceration, thereby prolonging the duration of
contact. Although natamycin is well absorbed
Pharmacokinetics
by the cornea, only small amounts are bioactive.
All polyenes are insoluble. They practically are not Despite that, natamycin is an effective ophthalmic
absorbed from gastrointestinal tract and mucous antifungal agent because the relatively high total
corneal drug concentration ensures that adequate topical, systemic and intraocular amphotericin
amounts of bioactive drug are available. B therapy is used, though it achieves very poor
concentrations in the posterior segment of the eye. 9
Therapeutic Uses
Adverse Effects
Polyenes are drugs of choice in the treatment
of fungal keratitis. Nystatin has limited use in Local
the treatment of ocular infections because it The toxic effects of topical amphotericin B
has poor ocular penetration and causes corneal
appear to be related in part to the effects of the
toxicity. Natamycin is the only polyene anti-
bile salt deoxycholate used as a solubilizer. They
fungal that is approved for topical application
include chemosis, burning, epithelial clouding,
for ocular fungal infection. It is available as a 5%
and punctate epithelial erosions. In extreme
suspension. Natamycin is most effective against
cases, the cornea may assume a greenish hue.
the filamentous fungi especially in most cases of
Intravenous administration causes phlebitis.
keratitis caused by Fusarium and Aspergillus.6
There are, however, reports of treatment failures Topical natamycin is usually well tolerated.
with these and other filamentous fungi. Yeasts Rarely, corneal toxicity manifested as a form of
such as Candida species tend to be less sensitive punctate keratitis may occur.
to treatment with natamycin than filamentous
fungi. Systemic
Amphotericin B is most efficacious in Amphotericin B causes chills and rigors with
the treatment of keratitis caused by yeasts, infusion. Often, antipyretics and anti-histamines
particularly Candida and Cryptococcus species It have to be administered to patients receiving
is less effective in filamentous fungal infections.6 infusion of amphotericin B. The serious adverse
The routes of administration of amphotericin B in
effect of this drug, which has limited its use,
the treatment of keratomycoses include topical,
is nephrotoxicity. For patients on long-term
subconjunctival, intracameral and intravenous.
treatment with amphotericin B, it is imperative
Topical amphotericin B has been used to treat
mycotic keratitis since 1959, although toxicity to monitor patient’s renal function.
has been a troublesome complication. Low
dilutions (0.15% and 0.05%) of amphotericin B Contraindications
have been shown to be efficacious and produce Polyenes are contraindicated in patients with
far less toxic effects than higher concentrations previous history of hypersensitivity towards it.
previously used. Subconjunctival administration Amphotericin B is to be used with caution in
of amphotericin B has been advocated for the very young or elderly patients and patients with
treatment of fungal keratitis and in severe cases, pre-existing renal disease to reduce the risk of
especially ulcers with anterior chamber reaction.7,8 nephrotoxicity.
However, the injections are quite painful and
poorly tolerated. Ulceration and necrosis of the
overlying conjunctival epithelium may occur. PYRIMIDINES
Intravenous administration carries a serious risk
of systemic toxicity including renal toxicity, Pyrimidines are antimetabolites which
chills, fever, phlebitis and anemia. For this reason, impair fungal DNA synthesis. Flucytosine
intravenous amphotericin B is rarely used in the (5-fluorocytosine) is a fluorinated pyrimidine
treatment of keratomycoses. and is the prototype drug for this drug class. First
Regarding fungal endophthalmitis, to preserve synthesized in 1957 as an antimetabolite for the
visual function and eliminate the fungal pathogen, treatment of leukemia, the antifungal properties
of flucytosine were first described by Grunberg of flucytosine are limited. It is effective against
and colleagues in 1963. Candida with some moderate activity against
Aspergillus. Because resistance to flucytosine
Mechanism of Action is a major problem among fungi, it is often not
effective as monotherapy and has to be used in
Flucytosine is a fungistatic drug. It is transported combination with other anti-fungal drugs such
across the fungal cell membrane by a specific as amphotericin B, natamycin and miconazole.10
permease. Once inside the cell, it is metabolized
by deamination to fluorouracil, a thymidine
Adverse Effects
analogue that blocks further fungal thymidine
synthesis, thereby impairing RNA and DNA Local
synthesis. Flucytosine has selective toxicity
toward fungal cells and not the mammalian cells Topical flucytosine is well-tolerated.
as it is not metabolized due to lack of cytosine
deaminase in mammalian cells.3 Systemic
Flucytosine causes gastrointestinal adverse effects
Antifungal Activity such as nausea, vomiting and diarrhea with oral
Flucytosine is effective against Candida spp. and administration. It is hepatotoxic and, therefore,
Cryptococcus. Monotherapy with flucytosine monitoring of the liver function is essential for
may result in fungal resistance. The mechanism patients on this drug. As with other hepatotoxic
of resistance is associated with the deficiency of drugs, withdrawal of the drug should be considered
specific permease required to transport the drug with increase in the levels of serum transaminases
into the cell. and alkaline phosphatase as these changes are
reversed when the drug is discontinued. At
concentrations higher than 100 μg/mL, flucytosine
Pharmacokinetics
can cause bone marrow suppression.10
Flucytosine is moderately soluble in water.
Given orally, the drug is well absorbed by the Contraindications
gastrointestinal tract. Therapeutic levels can be
achieved in adults with the administration of Flucytosine is contraindicated in patients who
a dose of 50–150 mg/kg/day in divided doses. have a previous history of hypersensitivity
Tissue penetration with 1% solution is good. towards it. It is also contraindicated in patients
Flucytosine is widely distributed in the body. with bone marrow suppression and should be used
It is mostly excreted unchanged by the kidneys cautiously in patients with liver dysfunction and
and can be cleared by hemodialysis. A topical renal impairment.
preparation is made by dissolving the contents
in a capsule of flucytosine in artificial tears. The
solution is filtered before use to remove any AZOLES
undissolved flucytosine. Flucytosine has been
used with success as a 1% solution topically inThiabendazole, an antiprotozoal drug was found
the treatment of keratitis. to have antifungal properties. This led to the
discovery of a potent and effective antifungal
class of azoles. Azoles are divided into two
Therapeutic Uses groups, imidazoles and triazoles (Table 10.2),
Flucytosine is best used as an adjunct therapy both have the same mechanism of action.
in the treatment of fungal keratitis. With a The most commonly used azoles in ophth
narrow anti-fungal spectrum, the clinical uses almology are clotrimazole, ketoconazole,
Table 10.2 Classification of azole antifungal agents
Imidazoles Triazoles
Systemic Topical Systemic Topical
Ketoconazole Miconazole Fluconazole Terconazole
Clotrimazole Itraconazole
Econazole Ravuconazole
Butoconazole Posaconazole
Bifonazole Voriconazole
Tioconazole
Oxiconazole
Fenticonazole
Sertaconazole
Sulconazole
miconazole, itraconazole, fluconazole and mechanisms such as the alteration of 14-α-sterol

voriconazole. demethylase, increased production of 14-α-sterol
demethylase and azole efflux.
Mechanism of Action
All azoles inhibit 14-α-sterol demethylase enzyme, Pharmacokinetics
which is involved in fungal ergosterol synthesis. Systemic Azoles
Therefore, they impair ergosterol biosynthesis for
the cytoplasmic membrane and cause accumulation The systemic azoles such as ketoconazole,
of ergosterol precursor 14-α-methylsterol. itraconazole, fluconazole and voriconazole
Methylsterol disrupts the structure of cytoplasmic are well absorbed from gastrointestinal tract
membrane and membrane associated enzymes and are widely distributed in tissues. They
responsible for the fungal growth.3 achieve adequate concentrations in the cornea
The imidazoles, except for ketoconazole, when administered topically, or orally. With
are fungistatic in vitro at low concentrations oral administration, it also achieves high
and fungicidal at high concentrations. The high concentrations in the aqueous humor. They
concentrations required for fungicidal effect is not are used in the treatment of systemic mycoses
easily attainable in the ocular tissue. Therefore, in because of their pharmacokinetic properties and
the treatment of ocular infections, the viewpoint good safety.
accepted is that the azoles have a fungistatic
effect. Topical Azoles
Topical azoles are usually poorly absorbed
Antifungal Activity from mucous membranes and are used for the
Azoles are generally active against Candida treatment of superficial mycoses. Azoles like
species, Aspergillus species, Histoplasma clotrimazole are used topically. Although they
capsulatum, Cryptococcus neoformans, Blast are well absorbed orally, their use is limited
omyces dermatitidis, Coccidioides species, to topical because of their significant systemic
Sporothrix schenckii, and Paracoccidioides toxicity. Ketoconazole primarily was introduced
braziliensis. in clinical practice as systemic antifungal drug
Secondary azole resistance emerges due to but it has been replaced by intraconazole and
prolonged use and is associated with several other triazoles because of their better safety
profile. Currently, ketoconazole is available with fluconazole or itraconazole is also a very
for topical use. Miconazole preparations for common mode of treatment in patients with
topical administration are available in the form fungal endophthalmitis. 14,15
of 1% drop in arachis oil or as cream (2%).
It is also available in an injectable form for Adverse Effects
subconjunctival injection, which can also be
used as topical application. Miconazole can Local
achieve high concentrations in the cornea and the Generally azoles are well tolerated. However,
aqueous humor with topical and subconjunctival patients can develop punctate keratopathy and
administration. It can be given intravenously to ocular irritation on prolonged use.
treat corneal fungal infections.
Therapeutic Uses Systemic

Fungal keratitis is very commonly caused by three Nausea, vomiting, diarrhea, abdominal cramps
fungal species: Aspergillus spp., Candida spp. and are most common adverse drug reactions
Fusarium spp. Ketoconazole is effective in the associated with azoles. Systemic azoles especially
treatment of keratitis and corneal ulcers caused by ketoconazole and itraconazole can cause serious
all three causative agents. It can be administered hepatotoxicity. The liver dysfunction is reversible
orally to treat corneal ulcers or as a topical agent on cessation of therapy. Monitoring of liver
at a concentration of 1–5%. Combined therapy of function is indicated in patients on long-term
oral ketoconazole and topical and subconjunctival oral ketoconazole and itraconazole treatment.
miconazole can be used effectively to treat corneal Voriconazole and some other azoles cause
ulcers. An alternative treatment to ketoconazole QT interval prolongation and may provoke
specially in yeast infections is fluconazole 0.5% arrhythmias specially if co-administered with
and miconazole 1%.11 Voriconazole is rapidly drugs that also prolong QT interval (amiodarone,
becoming the drug of choice for all fungal keratitis sotalol, quinidine, procainimide, etc.). Most of
because of its wide spectrum of antifungal activity systemic azoles are teratogenic (category C and D
and ability to achieve high concentration in of risk in pregnancy) and they are contraindicated
the cornea. 12 Combination therapy of topical during gestation.16 Allergic reactions such as rash,
amphotericin B eye drops with subconjunctival anaphylaxis, Stevens-Johnson syndrome may
injection of fluconazole is more effective than the occur during azole treatment.
use of topical amphotericin B eye drops alone and
may be recommended in complicated cases with
corneal perforation.13 Drug Interactions
Candida and Aspergillus are most common Azoles are potent inhibitors of cytochrome P450.
causative agents for fungal endophthalmitis. Thus, co-administration of azoles with drugs
The major problem in the treatment of fungal undergoing cytochrome metabolism may lead to
endophthalmitis is a highly variable penetration elevation of their plasma levels and appearance of
of systemically administered antifungal agents toxic effects. Drugs manifesting elevated plasma
into the posterior segment of the eye. Fluconazole levels due to co-administration with azoles include
and voriconazole are the drugs of choice because carbamazepine, digoxin, glipizide, haloperidol,
they achieve therapeutic concentration in the losartan, lovastatin, methylprednisolone,
vitreous for both, Candida and Aspergillus.9 omeprazole, phenytoin, quinidine, sirolimus,
The combination of intravitreal amphotericin B tacrolimus, warfarin, zidovudine and zolpidem.
ECHINOCANDINS Therapeutic Uses

The echinocandins are systemic antifungal agents The echinocandins are the drugs of choice in the
that were discovered in 1970s as the products of treatment of systemic yeast infection, especially
for empirical treatment of systemic candidiasis.
fungal fermentation. Three echinocandins are
Unfortunately echinocandins are of limited use
approved for clinical use currently: caspofungin,
in ophthalmology due to their poor intravitreous
anidulafungin, and micafungin. 17
penetration. Nevertheless, echinocandins may be
used in the treatment of fungal endophthalmitis
Mechanism of Action usually in combination with other antifungal agents.
All echinocandins noncompetitively inhibit 1,
3-β- and 1,6-β-D-glucan synthase, an enzyme
Adverse Effects
involved in the synthesis of 1,3-β-D-glucan, an Generally echinocandins are relatively safe
essential polysaccharide compound for the fungal and well-tolerated drugs. Micafungin and
cell walls. Changes in the cell wall structure due to anidulafungin show lower frequency of adverse
abnormality of glucan synthesis leads to osmotic drug reactions as compared to caspofungin.
instability and lysis of fungal cells.17 However, it might be explained by the longer
history of caspofungin’s clinical use compared
to two other echinocandins.19
Antifungal Activity There is insufficient data regarding the safety
The echinocandins show high fungicidal activity of caspofungin and other echinocandins in
against Candida spp. including the strains that pregnancy. Echinocandins belong to pregnancy
are fluconazole-resistant. Echinocandins also category C and should be avoided during
have also fungistatic activity against Aspergillus gestation and breast feeding.16
spp.
Drug Interactions
Pharmacokinetics Generally echinocandins neither serve as a
substrates nor are potent inducers/inhibitors of
All echinocandins have very low oral bioav cytochrome P450 and, therefore, have minimal
ailability and, therefore, they are administered only risk of involvement in drug-drug interactions even
intravenously.17 They have high protein binding in combinations with other antifungal agents.18
and are widely distributed in the body. However, Caspofungin slightly increases tacrolimus plasma
cerebrospinal fluid and intravitreous penetrations level, while no such effects of micafungin and
are minimal. 18 The clinical significance of anidulafungin have been reported 3.
low brain and ocular barrier penetration is
questionable. There are some reports of clinical GRISEOFULVIN
failure as well as successful use of caspofungin
monotherapy in the treatment of Candida albicans Griseofulvin is one of the oldest antifungal drug.
endophthalmitis.19 It was isolated in 1939 from some strains of
Following initial distribution, echinocandins Penicillium griseofulvum.
are metabolized in liver (caspofungin and
micafungin) and red blood cells (micafungin). Mechanism of Action
Metabolites are mostly excreted in the bile. Griseofulvin binds to tubulin and inhibits micro
They are not dialyzable and do not require dose tubule formation during mitosis, thereby affects
adjustment in patients with renal failure. fungal cell division. Thus, the mechanism of action
of griseofulvin is similar to that of vinca alkaloids Adverse Effects
but the sites of binding are different. Similarities
of the mechanisms of action make griseofulvin Griseofulvin is a relatively safe drug. The
potentially interesting as anticancer drug.20 most common adverse drug reactions due to
griseofulvin are headache, fatigue, vertigo and
peripheral neuritis. Other adverse effects include
Antifungal Activity
hepatotoxicity, neutropenia and severe skin
Griseofulvin is fungistatic and is most effective reactions (Stevens-Johnson syndrome, toxic
against dermatophytes including various species epidermal necrolysis). Estrogen-like effects have
of Microsporum (Microsporum audouinii, been observed in children.
Microsporum canis, Microsporum gypseum),
Epidermophyton (Epidermophyton floccosum), and Drug Interactions
Trichophyton (Trichophyton rubrum, Trichophyton
tonsurans, Trichophyton mentagrophytes, Griseofulvin induces hepatic cytochrome enzymes
Trichophyton interdigitalis, Trichophyton and, therefore, may reduce the efficacy of22the
verrucosum, Trichophyton megnini, Trichophyton drugs like warfarin and oral contraceptives .
gallinae, Trichophyton crateriform, Trichophyton
sulphureum, Trichophyton schoenleini). Contraindications
Griseofulvin is contraindicated in patients with
Pharmacokinetics severe liver failure and hypersensitivity to
Griseofulvin is used orally. It is highly lipophilic griseofulvin. Chronic use of griseofulvin causes
and is well absorbed from gastrointestinal tract. increased level of protoporphyrins, thus, it is also
Fatty meal increases the systemic bioavailability contraindicated in patients with porphyria.3
of griseofulvin. Bioavailability of microcrystalline

(Grifulvin V) and ultra-microcrystalline (Gris-
ALLYLAMINES
PEG) preparations of griseofulvin is reported to
be higher and this allows use of two-third of the Allylamines are synthetic antifungal agents
normal dose of griseofulvin. However, there is including systemic terbinafine and topical
currently no evidence that this lower dose confers naftifine, amorolfine, and butenafine.
any significant clinical differences with regard to
safety and/or efficacy.
Mechanism of Action
Griseofulvin is distributed and mainly deposited
in keratin precursor cells. Long-term persistence Allylamines inhibit the synthesis of ergosterol
of griseofulvin in keratin prevents fungal invasion by inhibiting squalene epoxidase, an enzyme
into the disease free tissues until they are replaced involved in ergosterol synthesis. Ergosterol is
by non-griseofulvin containing cells.3 essential for the structure of fungal cytoplasmic
membranes and interruption of its synthesis leads
Therapeutic Uses to disruption of cytoplasmic membranes.
Griseofulvin is indicated for the treatment of the

ringworm infections (Tinea corporis, Tinea pedis,
Antifungal Activity
Tinea cruris, Tinea barbae, Tinea capitis, and Tinea The antifungal spectrum of all allylamines is
unguium).21 In ophthalmology practice, griseofulvin similar to that of griseofulvin and includes
may be used for the treatment dermatomycoses species of Microsporum, Epidermophyton, and
affecting eyebrows and periorbital skin. Trichophyton.
Pharmacokinetics 3. Bennet JE. Antifungal agents. In: Brunton LL,

Chabner BA, Knollmann BC (eds). Goodman
Terbinafine is well absorbed, but its bioavailability and Gilman’s The Pharmacological Basis of
is significantly decreased due to first-pass Therapeutics, 12th edn. Mc Graw Hill Medical.
metabolism in the liver. Terbinafine is lipophilic 2011;1571–92.
and is well distributed in the tissues. It accumulates 4. Qu L, Li L, Xie H. Corneal and aqueous humor
in the skin, nails and fat. It is metabolized in liver concentrations of amphotericin B using three
by the cytochrome P450.3 different routes of administration in a rabbit
model. Ophthalmic Res. 2010;43(3):153–8.
5. Offner F, Krcmery V, Boogaerts M, Doyen
Therapeutic Uses C, Engelhard D, et al. Liposomal nystatin in
Naftifine, amorolfine, and butenafine are patients with invasive aspergillosis refractory
to or intolerant of amphotericin B. Antimicrob
administered topically in the form of a cream and
Agents Chemother. 2004;48(12):4808–12.
nail lacquer. Terbinafine is used topically as well
6. Tuli S S. Fungal keratitis. Clin Ophthalmol.
as systemically. Terbinafine is mostly used in the 2011;5:275–9.
treatment of tinea infections and onychomycosis.21 7. Carrasco MA, Genesoni G. Treatment of
Topical applications of terbinafine, naftifine, and severe fungal keratitis with subconjunctival
butenafine are sometimes used for the treatment amphotericin B. Cornea. 2011;30(5):608–11.
of cutaneous candidiasis. In ophthalmology 8. Yilmaz S, Ture M, Maden A. Efficacy of
terbinafine may be used in the treatment of intracameral amphotericin B injection in the
dermatomycosis of the periorbital skin. management of refractory keratomycosis and
endophthalmitis. Cornea. 2007;26(4):398–402.
9. Riddell J 4th, Comer GM, Kauffman CA.
Adverse Effects Treatment of endogenous fungal endophthalmitis:
Terbinafine is well tolerated and may be safely focus on new antifungal agents. Clin Infect Dis.
used even in children. Rarely, it may cause 2011;52(5):648–53.
hepatotoxicity and severe neutropenia. Stevens- 10. Vermes A, Guchelaar HJ, Dankert J. Flucytosine:
a review of its pharmacology, clinical indications,
Johnson syndrome may also occur.
pharmacokinetics, toxicity and drug interactions.
J. Antimicrob Chemother. 2000;46(2):171–9.
Drug Interations 11. M a n z o u r i B , Va f i d i s G C , Wy s e R K .
Terbinafine has a low potential for drug Pharmacotherapy of fungal eye infections. Expert
Opin Pharmacother. 2001;2(11):1849–57.
interactions.22 However, terbinafine is metabolized
12. Hariprasad SM, Mieler WF, Lin TK, Sponsel
by cytochrome so it may interacts with drugs
WE, Graybil JRl. Voriconazole in the treatment of
significantly affecting cytochrome P450 activity, fungal eye infections: a review of current literature.
such us phenobarbital, rifampin and cimetidine. Br J Ophthalmol. 2008;92(7):871–8.
13. Mahdy RA, Nada WM, Wageh MM. Topical
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MM, Souza CM, Riezman H, de Kruijff B, Tarai B, George VK, Fomda BA, et al. Fungal
et al. Natamycin blocks fungal growth by endophthalmitis: fourteen years’ experience from
binding specifically to ergosterol without a center in India. Retina. 2008;28(10):1400–7.
permeabilizing the membrane. J Biol Chem. 15. Khan FA, Slain D, Khakoo RA. Candida
2008; 283(10):6393–401. endophthalmitis: focus on current and future
antifungal treatment options. Pharmacotherapy. 20. Panda D, Rathinasamy K, Santra MK, Wilson L.
2007; 27(12):1711–21. Kinetic suppression of microtubule dynamic
16. Moudgal VV, Sobel JD. Antifungal drugs in instability by griseofulvin: implications for
pregnancy: a review. Expert Opin Drug Saf. its possible use in the treatment of cancer.
2003; 2(5):475–83. Proc Natl Acad Sci USA. 2005;102(28):
17. Sucher AJ, Chahine EB, Balcer HE. 9878–83.
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Ann Pharmacother. 2009; 43(10):1647–57. Pang KR, Tyring SK. Therapy of common
18. Denning DW. Echinocandin antifungal drugs. superficial fungal infections. Dermatol Ther.
Lancet. 2003; 4;362(9390):1142–51. 2004;17(6):517–22.
19. Eschenauer G, DePestel DD, Carver1 PL. 22. Albengres E, Le Louët H, Tillement JP. Systemic
Comparison of echinocandin antifungals. Ther antifungal agents. Drug interactions of clinical
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ChapteR 11
Drugs Used in Ocular
Pain and Inflammation
OVERVIEW available, since topical use is associated with

fewer adverse events as compared to systemic
As with several other clinical conditions, pain administration. Available topical preparations are
is also a frequent accompaniment of many listed in Table 11.8.
ophthalmic disorders. Pain localized to the eye Following better understanding of the
and surrounding structures shares causes, which mechanisms involved in pain generation and
are similar to the ones responsible for pain in transmission, recent strategies have targeted
other parts of the body such as trauma (including newer approaches for analgesia. Some of these
surgical), inflammation, and neoplasia. Raised are described in the later part.
intraocular pressure and refractive errors also
lead to pain. While correction of the underlying
cause is important for effective pain relief in the MECHANISMS OF PAIN
latter, pain control itself is an important priority
in the former. Pain is a subjective phenomenon generally
The two major classes of drugs that have long regarded as being associated with tissue damage,
been used for analgesic purpose are the “opiates” injury or inflammation. However, not only is pain
and the “non-steroidal anti-inflammatory drugs” often experienced in the apparent absence of any
(NSAIDs) or non-opioid analgesics. Both overt signs of such processes (e.g. neuralgias),
morphine (the prototype opiate) and aspirin (the the intensity of the pain experienced in the
earliest NSAID) are still in use but several new presence of tissue damage or inflammation can
members of each class have been developed over also exhibit wide variations. Thus, pain cannot
the years. Under certain circumstances some be considered simply to be a response to tissue
non-analgesic drugs may be used to relieve pain damage but rather a complex interplay of
(e.g. anticonvulsants, tricyclic antidepressants processes comprising of physiological, neural,
or serotonin/norepinephrine reuptake inhibitors psychological and emotional components.
for neurogenic pain, ergot alkaloids for migraine Despite the complexities involved, we now
and nitroglycerine for pain of angina pectoris) but have a fairly clear understanding of many of the
these are not classified among the analgesic drugs. processes involved in the initiation, the pathways
In this chapter, we discuss the pharmacology of transmission and the central mechanisms
of the ‘classical’ analgesics viz. the opiates pertaining to the perception of pain. Several
and NSAIDs. The use of opiates in ophthalmic chemical mediators that either stimulate or
practice does not differ greatly from its use in enhance the sensitivity (thereby lowering their
other fields, hence these are only dealt with in excitation threshold) of nociceptors and thus, play
brief. NSAIDs find a greater use, particularly a role in the initiation and amplification of the
those for which suitable topical formulations are pain stimulus are well recognized. Similarly, the
Drugs Used in Ocular Pain and Inflammation 157
processes involved in the transmission of the pain Mechanism of Action
stimulus from the site of generation to the central
nervous system and the mechanisms, chemical Opioid analgesics produce analgesia by binding
signaling molecules and receptors involved to specific G-protein coupled receptors. These
therein, leading to the perception of pain, have receptors are classified into three types and
been worked out in substantial detail. The role denoted by the Greek characters μ (mu), К (kappa)
of prostaglandins, in the generation of the pain and δ (delta). Each of these receptors also has
stimulus and that of the endogenous peptides subtypes. The μ and δ have two subtypes viz. μ1,
and their receptors in the central processing of μ2 and δ1, δ2 while К has three subtypes К1, К2
pain have been the subject of great attention and and К3. These receptors are located in regions of
also the major targets for pain control strategies. the brain and spinal cord, which are involved in
Despite so many advances, the two major groups the transmission and processing of pain. Opioid
of analgesics that have dominated for more than receptors are also present at nerve terminals in the
a century, and still continue to dominate, are the periphery and may be involved in the modulation
NSAIDs, which inhibit prostaglandin synthesis, of release of neurotransmitters from the sensory
and opiate derivatives (including synthetic) which nerve terminals. The inhibition of the release of
act on specific receptors (mu, kappa and delta) substance P in the dorsal horn of the spinal cord
that are the targets of endogenous opioid peptides by morphine is one of the mechanisms involved
viz. endorphin and encephalin. Other targets, in its analgesic effect. Although all the opioid
which have of late received attention for possible receptors are involved with pain regulation, the
approaches towards analgesic drug development, principal receptor for analgesic action of opioids
include ion channels involved in nociceptive appears to be the μ receptor.
nerves, neuropeptides like somatostatin, glutamate Physiologically the opioid receptors are
receptors and cannabinoid receptors. Most of targets for a group of peptides, which are richly
these are still under experimental or early clinical present in regions of the CNS concerned with pain
evaluation. modulation and themselves possess analgesic,
sedative and other pharmacological properties
that are similar to the opioids. These peptides,
OPIOID (NARCOTIC) ANALGESICS
therefore, have been termed as the endogenous
For many centuries crude opium, derived from the opioid peptides.
opium poppy, has been in use (and abuse) for its Three families of peptides (Table 11.1) derived
analgesic, sedative and euphoric effects. Serturner from pre-proopiomelanocortin (POMC) have
isolated the pure alkaloid in 1803 and named been characterized and studied in extensive detail
it morphine (after Morpheus the Greek god of viz. the endorphins, encephalins (leu-enkephalin
dreams). It is surprising that even after more than and met-enkephalin) and the dynorphins. These
two centuries, during which tremendous advances peptides display varying affinities for the opioid
have been made in the field of synthetic drugs, not receptor subtypes but all of them are involved
only is morphine still in clinical use but is also in endogenous pain control mechanisms and are
the standard against which all other analgesics released in response to painful and other stressful
of this class are compared. Several derivatives stimuli. Besides, they are also involved in other
obtained from natural sources, by chemical physiological functions.
modifications of the opium alkaloids or through In addition, another receptor-ligand system
de novo synthesis, sharing similar properties and has also been identified. The endogenous ligand
mechanisms of action are grouped together as for this system is nociceptin, which differs from
opioids (the term ‘opiate’ is reserved for drugs dynorphin only marginally with the N-terminal
obtained from the opium plant). tyrosine being absent. This receptor ligand system
Table 11.1 Opioid receptor subtypes and the opioid peptides
Endogenous opioid peptide Receptor affinity Function

Endorphin μ > k or d Analgesia (spinal and supraspinal), respiratory depression,
decrease in GI motility, neuroendocrine modulation
Enkephalin d > μ or k Analgesia (spinal and supraspinal), neuroendocrine
modulation
Dynorphins k > μ or d Analgesia#, decrease in GI motility, psychotomimetic
effects
#
Dynorphin has also been reported to produce a hyperalgesic action at the spinal dorsal horn level through k receptors
is widely represented in the central nervous Morphine: The Prototype Opioid

system and also in the periphery. However, in Drug
contrast to endorphins, it opposes μ receptor
mediated pain suppression besides involvement Morphine is the major analgesic drug present
in other behavioral functions. in crude opium derived from the poppy plant. It
Interaction of opioids with the G protein acts on all three subtypes (μ, К and δ) of opioid
coupled receptors affects gating of ion channels to receptors, possesses powerful analgesic actions
modulate ion fluxes across neuronal membranes. and also displays the full range of effects of opioid
Receptor actions of opioids bring about a drugs on other tissues and systems. It is, therefore,
closure of voltage dependent Ca++ channels on taken as a prototype for this class against which
presynaptic nerve terminals causing a decrease all other drugs are compared. Codeine, is also
in the neurotransmitter release. An inhibitory present in the extract of the opium plant but
action on presynaptic release of neurotransmitters has substantially lower analgesic activity. Other
by opioids has been demonstrated for several opioids may differ from morphine in their
neurotransmitters including norepinephrine, analgesic as well as other actions because of one
serotonin, acetylcholine, substance P and or more of the following reasons:
glutamate. Post-synaptically, an increase in i. Preferential affinity for only particular (and
K+ efflux (by opening K+ channels) by opioids not all) receptor subtypes
hyperpolarizes the membrane to reduce neuronal ii. Partial agonist action at the opioid receptors
activity. Sites that are concerned with the on which they act
regulation of pain exhibit a rich distribution of iii. Mixed actions, i.e. agonist at one or more
opioid receptors as shown in Table 11.2. receptor subtype and antagonist at other/s
Table 11.2 Distribution of opioid receptors and their role in analgesia
Site Suggested role

Spinal cord (substantia gelatinosa) Suppression of upward transmission of afferent sensory information
from the periphery
Medial hypothalamus Modulate perception of deep (poorly localized) pain
Limbic system Not involved directly with analgesia but may be important for emotional
reaction to painful stimuli
Peripheral sensory nerve terminals Inhibit release of pro-inflammatory substances
Classification Pharmacokinetics
Due to differences in receptor actions and Absorption: Opioids are most frequently
pharmacokinetics, opioids display differences administered through the parenteral route. Most
in their efficacies for pain relief, with some like opioids are well absorbed after intramuscular
morphine and fentanyl possessing powerful or subcutaneous administration. Morphine is
analgesic actions, even against high intensity absorbed from the gut after oral administration
pain, while others, like codeine and pentazocine, although the absorption is slow, often erratic and
display only limited effects. Further, differences subject to considerable first-pass metabolism.
are also observed in their propensity for inducing Consequently the oral dose of morphine is
adverse effects. Opioids can thus be classified usually several folds higher than its equivalent
either on the basis of their pain relieving potential parenteral dose. Extended release forms of
(Table 11.3) or on the basis of their receptor morphine are often used orally to achieve more
actions (Table 11.4). The former is more relevant consistent plasma levels. Codeine does not
with regard to the choice for clinical use while the undergo extensive first pass metabolism and is
latter is important for an understanding of their used orally.
actions and some of their adverse effects. For Distribution: Following absorption opioids
example, the drugs like buprenorphine, which rapidly enter most tissues with greater localization
have partial agonist action at μ receptors, have in the highly perfused tissues such as the brain,
less potential for severe respiratory depression as lungs , liver, kidney and spleen. Morphine is less
compared to full agonists. Alternatively, opioids lipophilic than many other commonly used opioids
can also be classified according to their chemical and only a small fraction crosses the blood brain
structure. barrier. In contrast, other agents like methadone,
fentanyl and heroin are more lipophilic and
Table 11.3 Classification of opioids based on their readily enter the brain. Morphine, however,
efficacy crosses the placental barrier and can affect the
High efficacy Morphine, meperidine, fetus and is, therefore, not recommended during
fentanyl, methadone, labor. Highly lipophilic agents like fentanyl tend
nalbuphine, buprenorphine
to accumulate in fatty tissue, especially following
Moderate efficacy Hydrocodone, oxycodone, high doses or continuous perfusion.
pentazocine
Metabolism: Conjugation with glucuronic
Low efficacy Codeine acid in the liver converts morphine to more
Table 11.4 Classification of opioids based on their receptor actions
Agonists Partial agonists Mixed agonist-antagonists Antagonists

Morphine (μ,k,d) Buprenorphine (μ) Pentazocine (P-Ag k; Ant μ, d) Naloxone (μ, k, d)
Meperidine (μ,k) Nalbuphine Naltrexone
Fentanyl Butorphanol Nalmefine
Alfentanil Naloxonazine
Sufentanil
Ramifentanil
Methadone
Oxycodone
Codeine
Propoxyphene
Heroin
P-Ag: partial agonist; Ant: antagonist

polar forms, which are rapidly excreted by the affinity for μ receptors display a range of effects
kidneys and to a lesser extent in bile. Morphine- related to the central nervous system.
3-glucuronide, the major metabolite, exhibits Analgesia: Opioids are effective in relieving both
some neuroexcitatory properties, which are not the sensory as well as emotional components of
entirely mediated through opioid receptors. Up pain. Through a combination of effects at the
to 10% of morphine gets converted to morphine- spinal and supraspinal levels they cause not only
6-glucuronide, which shows considerably more an increase in the threshold for pain perception by
potent analgesic potency as compared to the the brain but also alter the emotional reaction to
parent compound. These metabolites are not pain whereby the awareness of pain sensation is
considered to be of significance for effects no longer unpleasant and, thereby, more tolerable.
following acute administration since being Euphoria: Morphine produces a strong sense of
polar they are not able to readily cross the blood well-being, a floating sensation and a decrease in
brain barrier. Administration of large doses or in anxiety especially after intravenous administration
patients with compromised renal functions the – the major reason for its abuse by intravenous
accumulation of these metabolites may result drug users. As opposed to euphoria, dysphoria –
in adverse effects. Morphine administration an unpleasant state of restlessness – may result in
is not recommended in neonates because the some individuals.
conjugating enzymes are not fully developed. Sedation: Mental clouding, drowsiness and
Pethidine (meperidine) and fentanyl and other induction of sleep are commonly associated with
phenylpiperidine derivatives are primarily administration of morphine. These effects are
degraded by hepatic oxidative metabolizing potentiated by concomitant use of other CNS
enzymes to inactive products. Normeperidine, the depressants like sedative-hypnotics.
metabolite of pethidine has potential for inducing Respiratory depression: Morphine and other
seizures and its accumulation after high doses or opioid drugs can produce respiratory depression
in patients with compromised renal functions may by decreasing the sensitivity of neurons in the
be dangerous. The pharmacokinetic properties of respiratory center in the brain stem to carbon
some commonly used opioids are given below dioxide. This occurs with usual doses of morphine
(Table 11.5). and becomes more pronounced with increasing
doses. Very high doses can result in a complete
suppression of respiratory function. Failure of
Pharmacological Actions
respiration is the most common cause of death
The most notable effects of opioid agonists are on from opioid overdose. Thus, respiratory depression
the central nervous system. Members that have constitutes the most important limitation to
Table 11.5 Pharmacokinetic properties of some commonly used opioids
Drug Approximate equivalent Route/s of administration Duration of

doses (parenteral) analgesic action
Morphine 10 mg IV, IM, SC, PO 4–5 h
Meperidine 100 mg IM, IV, SC 3–4 h
Fentanyl 0.1 mg IV 0.75–1.0 h
Pentazocine 30 mg IV, IM, PO Up to 4 h
Buprenorphine 0.3 mg IV,IM Up to 8 h
Codeine 30–60 mg Oral 3–4 h
effective use of opioids for pain control. The Histamine release: Morphine releases histamine
presence of increased intracranial tension or from the mast cells. This often results in urticaria,
chronic obstructive pulmonary disease (COPD) vasodilatation and sweating following intravenous
increases the susceptibility for this untoward administration.
outcome. Some opioids like buprenorphine
exhibit a ‘ceiling effect’ in this regard. Thus with Tolerance and Dependence
increasing doses the respiratory depressant effects
On continued use of morphine and other opioids,
seems to level off, providing some margin of safety.
tolerance often develops for some of the effects.
Suppression of cough reflex: Suppression of
Effects which display a high level of tolerance
cough reflex is a well known effect of opioids
development include analgesia—the major
and codeine in particular is used as an antitussive.
therapeutic purpose for which opioids are
The mechanism of cough suppression appears to
generally used—necessitating an increase in
be somewhat different from the analgesic effects
dosage to achieve an acceptable therapeutic
of opioids and does not correlate with analgesic
effect, euphoria, sedation, nausea and vomiting
potency.
and respiratory depression. Cross tolerance
Emesis: Morphine stimulates the chemoreceptor
among different members is commonly seen.
trigger zone in the area postrema and produces
Tolerance is minimal or absent for constipation
nausea and vomiting.
and miosis.
Miosis: Miosis is produced by most opioids. An
Emergence of tolerance following frequent and
increase in parasympathetic influence on the eye
repeated use of opioids is also accompanied by the
due to stimulation of μ and К receptors in the
development of physical dependence. Stopping the
Edinger-Westphal nucleus of the oculomotor
drug in such individuals, results in the appearance
nerve is responsible for this effect. Pin-point
of a ‘withdrawal syndrome’ characterized by
pupils are a diagnostic sign for opioid poisoning
restlessness, excitatory symptoms and drug
even in chronic drug users since little tolerance
craving. The mechanisms for development of
develops to this effect.
tolerance and physical dependence are complex and
Other CNS-mediated effects of opioids include
involve an interplay of adaptive changes occurring
alterations of homeostatic regulation of body
at the level of receptors, neurotransmitters and
temperature, supraspinally mediated exaggeration
other molecular targets.
of the tone of trunk muscles, a central depression
of vasomotor tone and neuroendocrine effects.
opioids also produce several peripheral effects, Therapeutic Uses
which include effects on: Analgesia: Morphine and other high efficacy
Smooth muscles: Intestinal motility is diminished opioids (Table 11.3) occupy an important place
due to an increase in the tone of the circular in the management of moderate to severe pain.
smooth muscle through an action on the enteric Constant and sustained pain responds better
nervous system leading to constipation. Some while sharp, intermittent pain appears to be less
opioid congeners with restricted peripheral effectively controlled with opioids. The pain
smooth muscle actions like loperamide and associated with cancer almost always requires
diphenoxylate are indeed used as antidiarrheals. the use of opioid analgesics on a long-term basis
Constriction of the biliary smooth muscle as well and some degree of tolerance and dependence are
as the sphincter of Oddi may result in biliary colic. often encountered during such use. However, the
Uterus: Labor is prolonged by opioid analgesics. possibility of inducing tolerance and dependence
Renal effects: A decrease in renal plasma flow should not constrain the use of opioid analgesics
caused by opioids results in a decrease in renal in such conditions since the benefits in terms of
function. relief of pain and the consequent enhancement of
quality of life far outweigh the risks associated commonly encountered during opioid use. With
with dependence in these patients. Severe high doses severe respiratory depression can be a
visceral pains arising from conditions such serious and life threatening problem. Patients with
as biliary and renal colics and the pain of respiratory insufficiency are especially prone to
myocardial infarction often require opioids. respiratory depressant effects and require careful
Opioids are also used during obstetric labor but monitoring if opioids have to be used at all in this
caution is required since opioids can cross the group. Other adverse effects include dysphoria
placenta and cause fetal respiratory depression. occurring occasionally, postural hypotension
Meperidine (pethidine) is less likely to produce which is exacerbated by hypovolemia, itching
fetal respiratory depression and is preferred over and urticaria, an elevation of intracranial pressure
morphine for obstetric use. and acute urinary retention in patients with benign
Acute pulmonary edema: Dramatic relief of prostatic hyperplasia. Development of tolerance
dyspnea can be achieved in pulmonary edema and physical dependence (see above) require
associated with acute left ventricular failure consideration during chronic opioid use.
with administration of intravenous morphine.
A decrease in anxiety and reduced cardiac Contraindications
preload and afterload (due to reduced venous and
arteriolar tones) contribute to these effects. The use of opioids in certain conditions might
Diarrhea: Morphine has a constipating effect constitute an increased risk for adverse effects and
due to effects on intestinal motility and circular toxicity. Under such situations their use is either
smooth muscle tone thus providing effective contraindicated or, in case there is no alternative
control of diarrhea. Synthetic derivatives such to their use, extreme caution and monitoring is
as diphenoxylate and loperamide, which have required.
relatively selective gastrointestinal action with Head injury: In head injury, the intracranial
minimal effects on the central nervous system, pressure is usually raised. Opioids can further
are used as antidiarrheals. worsen this by producing dilatation of cerebral
Cough suppression: Opioids suppress cough by vessels due to their depressant effects on
a central action at doses lower than those required respiration and consequent carbon dioxide
for analgesia. Codeine has greater antitussive retention. Additionally, the CNS effects of opioids
action as compared to morphine. Synthetic can complicate the signs of altered consciousness
derivatives such as dextromethorphan and making identification and interpretation of the
levopropoxyphene are more selective as cough clinical signs of the head injury difficult.
suppressant and are devoid of other opioid effects. Reduced pulmonary function: Respiratory
Anesthesia: Opioids have important applications depressant effects of opioids can lead to acute
in anesthesia both as premedication and as a respiratory failure in patients with compromised
component of the anesthetic regimen. In addition, respiratory function and reduced respiratory
epidural and subarachnoid application of opioids reserve such as those with emphysema and
is often used for producing regional analgesia for COPD. Bronchoconstriction might further
operative purposes or for pain control. aggravate respiratory insufficiency in COPD and
asthma patients.
Adverse Effects Impaired hepatic or renal functions: The half-
The adverse effects of opioids are generally life of morphine and other opioids is prolonged
an extension of their pharmacological actions. in the presence of reduced hepatic and renal
Thus sedation, respiratory depression, nausea, functions. Consequently, accumulation of the
vomiting and constipation are the adverse effects parent drug and/or active metabolites is likely to
occur if this is not compensated by an adequate μ opioid receptors and lower activity on δ and К
downward adjustment of the dose. receptors. Several other non-peptide antagonists
Combination of more than one opioids: Since have been developed such as β-flunaltrexamine,
the mechanism of action of all opioids is similar, which is relatively specific for μ receptors and
a simultaneous use of more than one opioids naltrindole a δ receptor antagonist. The major
is not justified and may not yield additional utility of opioid receptor antagonists is in the
therapeutic benefit while increasing the risk of management of opioid overdose.
additive toxicity. Further, if a partial agonist or
mixed agonist-antagonist (e.g. pentazocine) is Topical Ocular Use of Opioids
administered together with a full agonist (e.g. Systemic use of opioids in ophthalmic practice is
morphine) the combined analgesic effect might generally limited to pain control following surgery.
actually be reduced. Opioids can, however, be However, there is some clinical and experimental
combined with other non-opioid analgesics data to support potential topical use of opioids
(NSAIDs) for additive effects. for ophthalmic pain control.1 Topical opioids
have been shown to alleviate pain following
Drug Interactions corneal abrasions without significantly delaying
corneal healing.2 Moreover, topical opioid use
Concurrent administration of opioids with other
may also have application in lowering intraocular
sedative hypnotic drugs tends to potentiate the
pressure and in reversal of mydriasis following
CNS and respiratory depressant effects. Increased
an ophthalmic examination. Opioid antagonist
sedation is also encountered with combined use
naltrexone might have a potential use in enhancing
of opioids and tricyclic antidepressant drugs.
corneal wound healing.3 Further development
Monoamine oxidase (MAO) inhibitors used
of opioid formulations for ophthalmic use
either during therapy with opioids (particularly
might provide safe alternatives for treatment of
meperidine), or within the last 14 days may result
ophthalmic pain, glaucoma and corneal wound
in hyperpyrexia and hypertension.
healing, without the concomitant adverse effects
associated with systemic opioid use.
Tramadol
Tramadol is a synthetic drug, which produces
NON-STEROIDAL
centrally mediated analgesia like the opioids but
has only a weak agonist activity at μ-receptors. ANTI-INFLAMMATORY DRUGS
Its analgesic action is thought to be related more (NSAIDs; NON-NARCOTIC
to its serotonin re-uptake blocking activity. It is ANALGESICS)
orally effective for mild to moderate pain with
less risk for respiratory depression. It is, however, Non-steroidal anti-inflammatory drugs (NSAIDs)
associated with an increased risk of seizures and have an important place in ophthalmic practice
is not recommended for patients with history of for the treatment of intraocular inflammation.
seizures. The use of aspirin and other salicylic compounds
for the treatment of ophthalmic inflammation has
been described almost a century ago.4 The time
Opioid Antagonists
since then has seen the development of many
Structural modifications of morphine and other other drugs with anti-inflammatory, analgesic
opioid drugs have yielded pure opioid receptor and antipyretic properties. While traditionally
antagonists like naloxone, naltrexone and these drugs have been employed via the systemic
nalmefine. These agents have high affinity for route of administration, the availability of topical
preparations for some of them has promoted the leukotrienes, in the process of inflammation
renewed interest in their use for ophthalmic which occurs in response to tissue insult. PGs
purposes. lower the threshold of the nociceptors of the C
fibers and inhibition of PG synthesis by NSAIDs
Pharmacokinetics reverses this sensitization of pain receptors to
mechanical and chemical stimulation.
NSAIDs are rapidly absorbed following oral Two isoforms of cyclooxygenase enzyme
administration and are readily distributed to (termed COX-1 and COX-2) are known to occur.
most tissues. Following entry into circulation COX-1 has been identified as the constitutive
most NSAIDs are extensively bound to plasma or ‘house-keeping’ isoform involved with
proteins. Peak concentrations are achieved physiological and homeostatic functions while
between 1–3 hours for different drugs. In general, COX-2 is induced during the inflammatory process
food delays absorption but peak concentrations and has pro-inflammatory actions. Although a
are usually unaffected. Plasma half-life for most third isoform, COX-3, of cyclooxygenase, has
is between 2–4 hours but may be longer for some also been described5 with an attempt to explain the
like naproxen (14 hours) and meloxicam (upto 20 analgesic and antipyretic action of acetaminophen
hours). The half-life of aspirin can be prolonged to – a weak inhibitor of COX-1 and COX-2 in the
more than 15 hours with toxic doses as compared periphery – its exact significance still remains
to around 1 hour with the therapeutic doses. controversial.
NSAIDs are mostly biotransformed by the hepatic Aspirin, the prototype NSAID, irreversibly
microsomal enzymes. Unchanged drug and the inhibits both COX-1 and COX-2. Other older
metabolites are eliminated by the kidneys. In NSAIDs are also COX inhibitors with little
patients with compromised liver function or renal selectivity for either COX-1 or COX-2. In
failure the elimination may be greatly delayed contrast to aspirin, the inhibition of COX by other
leading to an increased risk for adverse effects. NSAIDs is reversible. Some NSAIDs possess
Sulindac, a prodrug, is transformed to the active additional mechanisms, which possibly contribute
form through metabolism. to their anti-inflammatory effects. Recognition
of separate identities and functions of the two
Mechanism of Action isoforms triggered the development of selective
Aspirin and other NSAIDs produce anti- COX-2 inhibitors with the inherent hope that
inflammatory action primarily by inhibiting such agents would provide anti-inflammatory
cyclooxygenase (COX), which is involved in
the synthesis of prostaglandins (PGs). PGs are
autacoids that are synthesized by almost all
tissues for a variety of physiological purposes.
Arachidonic acid, the precursor for PGs, is a
component of the cell membrane phospholipids,
and is released by the action of phospholipase
A 2 and other hydrolases on cell membranes.
Free arachidonic acid is metabolized along two
separate metabolic pathways, viz. COX pathway
– to produce PGs, prostacyclin and thromboxane Figure 11.1 Arachidonic acid metabolism and generation
(TXA) – and the lipoxygenase (LOX) pathway, of inflammatory mediators
The generation of prostaglandins and leukotrienes from
to yield leukotrienes (LTs; Fig. 11.1). While PGs
arachidonic acid through the actions of COX and LOX,
have a diverse range of physiological functions, respectively, and some of the mechanisms by which PGs and
they are also intimately involved, together with LTs produce inflammation is shown.
action with a reduced liability for adverse effects may also be involved with the actions of some
as compared to non-selective COX inhibitors. of them. Inhibition of interleukin-1 actions on
Selective COX-2 inhibitors are comparable the hypothalamic thermoregulatory centers is
with non-selective members with regard to their considered to be mechanism responsible for
anti-inflammatory activity with greater safety antipyretic action of aspirin.
in terms of gastrointestinal adverse effects.
Selective COX-2 inhibitors do not possess anti- Pharmacological Actions
platelet-aggregatory activity. NSAIDs are usually
classified on the basis of their chemical structure The major pharmacological effects of NSAIDs
and COX selectivity (Table 11.6). can be summarized as anti-inflammatory,
Inhibition of COX is the common mechanism analgesic, antipyretic and antiplatelet. Aspirin,
shared by all NSAIDs but additional mechanisms which irreversibly inhibits COX, displays all
Table 11.6 Classification of NSAIDs

Class Comments
Salicylates
Aspirin Salicylate is the anti-inflammatory metabolite
Diflunisal Not metabolized to salicylic acid
Indole acetic acid derivatives Very potent; high toxicity; ocular preparation available
Indomethacin Prodrug
Sulindac (prodrug) Potent analgesic; ocular preparation available
Ketorolac
Etodolac
Propionic acid derivatives Better tolerated as a class
Ibuprofen Anti-inflammatory and analgesic
Fenoprofen
Ketoprofen
Naproxen
Flurbiprofen Ocular preparation available
Phenylacetic acid derivatives
Diclofenac Ocular preparation available
Fenamates
Mefenamic acid Efficacy, GI side-effects similar to aspirin
Meclofenamate
Nepafenac Ocular preparation available
Oxicam derivatives
Piroxicam Long half-life; single daily dose is effective
Meloxicam Relatively more selective for COX-2
Para-aminophenol derivative*
Acetaminophen Weak inhibitor of COX ; only analgesic and antipyretic
Selective COX-2 inhibitors#
Celecoxib Inhibits CYP2D6
Valdecoxib Inhibits CYP2C9; increased risk of stroke, MI
Ocular preparations for topical ophthalmic use are available only for some NSAIDs.
* Does not have anti-inflammatory activity. Central actions may be involved in its analgesic and antipyretic actions.
Use of some COX-2 inhibitors has been linked with increased risk for vascular accidents and rofecoxib was withdrawn from
#
clinical use.
these actions and is considered as the prototype hypothalamic area. PGE2 formed in the region
against which all other drugs are compared. of the preoptic hypothalamus in response
The relative degree of these actions may vary to these cytokines cause an elevation of the
in different members. For example, while thermoregulatory ‘set point’ resulting in an
ibuprofen produces analgesic, antipyretic and elevation of body temperature. Inhibition of PGE2
anti-inflammatory effects, relatively higher doses synthesis by NSAIDs reverses this response to
are usually necessary for anti-inflammatory produce an antipyretic action.
effects. Although all non-selective COX inhibitors Antiplatelet Action: Aspirin irreversibly
inhibit platelet function, only aspirin can do so acetylates platelet COX-1 causing suppression
in a sustained manner and in low doses due to of thromboxane A 2 (TXA 2 ) formation and
irreversible inhibition of the enzyme in platelets, consequent loss of platelet function. Adult
thus making it therapeutically relevant. NSAIDs platelets lack the enzymatic machinery for
have also been shown to reduce generation of free fresh synthesis of COX, therefore, once it is
radicals, adhesion molecules and cytokines. But inhibited by aspirin the platelet is unable to
these effects are seen at higher concentrations and synthesize TXA2 and suffers an irreversible loss
their relevance to the pharmacological effects is of its capacity to aggregate with consequent
a subject of debate. prolongation of bleeding time. The bleeding time
Analgesic Action: Several chemical mediators remains prolonged till a sufficient number of fresh
released during tissue injury or inflammation platelets with functional COX are formed and
are responsible for eliciting the pain response. released. The duration of effect is thus dependent
These include bradykinin, serotonin, leukotrienes, upon the turnover rate of platelets and may last
neuropeptides, prostaglandins and other for 4–7 days after cessation of administration. The
mediators. PGE2 and PGI2 formed as a result dose of aspirin required for antiplatelet action is
of induction of COX-2, sensitize the peripheral much lower (less than 100 mg/day) as compared
nociceptors and increase their excitability. The to the anti-inflammatory or antipyretic doses.
reversal of nociceptor sensitization by inhibition Other NSAIDs, which are reversible inhibitors
of COX-2-induced PG synthesis is thought to of COX do not have such long lasting antiplatelet
be the major determinant for the peripheral effects while selective COX-2 inhibitors as well
analgesic action of NSAIDs. A central component as acetaminophen are devoid of this property.
in the analgesic action of NSAIDs has also been
suggested and involves similar effects at spinal
Therapeutic Uses
and supraspinal levels to reduce PG mediated
central sensitization, which might contribute to Analgesic: NSAIDs are used for analgesic,
hyperalgesia and allodynia. antipyretic and anti-inflammatory purposes in
Anti-inflammatory action: Increased PGE2 and a wide variety of conditions. They are effective
PGI 2 synthesis during inflammation, mainly against mild to moderate pain of somatic origin
through induction of COX-2 contributes, together especially where the pain is associated with
with other mediators, to local vasodilatation, inflammation. The response to moderate or
increase in vascular permeability and infiltration severe visceral pain is often not satisfactory and
of leucocytes, thereby sustaining the inflammatory NSAIDs can be combined with opioid analgesics,
process. By inhibiting PG synthesis, NSAIDs tend whereby, they synergistically enhance the
to reverse the inflammation. analgesia providing improved pain control and a
Antipyretic Action: Increased formation of consequent reduction of opioid dose requirement.
cytokines such as interleukins, tumor necr Such combinations are often employed for the
osis factor and interferons destabilizes the treatment of cancer pain. Acetaminophen, is
thermoregulatory mechanisms at the preoptic devoid of any appreciable anti-inflammatory
activity and is used mainly for its analgesic and old platelets) after aspirin is stopped, a fact that
antipyretic actions. It is well tolerated and is has to be borne in mind, if a surgical procedure
almost free from GIT irritation, which together is planned.
with its over-the-counter availability, makes it Besides their above mentioned uses, NSAIDs
the most widely used analgesic. Although safe have also been found to be of some value in other
in usual doses, in very high (toxic) doses or in conditions, which include systemic mastocytosis6
presence of pre-existing hepatic damage, it can and prevention of colorectal cancer.7
lead to severe hepatic cellular necrosis due to
a toxic metabolite N-acetyl-p-benzoquinone. Adverse Effects
Ketorolac is another NSAID that is recommended
mainly as an analgesic, although it has significant Major adverse effects of aspirin and other non-
anti-inflammatory activity. It has strong analgesic selective COX inhibitors are related to gastric
action and can substitute for opioids for relief of irritation and intolerance. Microscopic blood
post-surgical pain in some cases. loss in the feces is common with aspirin therapy
Antipyretic: Aspirin, acetaminophen and some but frank ulceration of the gastric and duodenal
other NSAIDs have an important place in the mucosa also occurs. Locally present PGs in
control of pyrexia of varied origins. Central the gastric mucosa normally serve a protective
mechanisms are thought to be involved in this function against mucosal damage and the
effect and not all NSAIDs are equally effective loss of this protection due to inhibition of PG
as antipyretics. synthesis, besides the direct irritant effects of
Anti-inflammatory: NSAIDs have a major NSAIDs, contributes to the mucosal damage. As
role in the treatment of somatic inflammatory mentioned earlier, selective COX-2 inhibitors and
disorders most notably rheumatoid arthritis. acetaminophen have a better safety profile in this
Therapeutic benefits in this situation result from respect. Bleeding time is increased by NSAIDs
reduced inflammation as well as pain relief. due to their inhibitory effects on platelet TXA2
However, when used for this purpose, NSAIDs synthesis. This can manifest as easy bruising
have to be employed for relatively longer periods or enhanced bleeding following trauma or
and are thus more likely to give rise to adverse surgical procedures as also the enhanced risk of
effects. All NSAIDs are more or less equally intracranial bleeds.
effective as anti-inflammatory agents but may NSAIDs are generally regarded as nephr
differ in their adverse effects and tolerability. otoxic especially in individuals with pre-
Selective COX-2 inhibitors have lower potential existing renal or hepatic disease, congestive
for adverse gastrointestinal effects but concerns heart failure, cirrhosis or other conditions
remain about the increased incidence of stroke associated with decreased renal perfusion.
and MI with their use and have led to the In such situations PGs serve a critical role
withdrawal of some members (rofecoxib) for in maintaining renal perfusion and by
this reason. inhibiting PG synthesis, NSAIDs can severely
Antiplatelet Action: Among the NSAIDs, only compromise renal function. High doses of
aspirin is used for antiplatelet and cardioprotective aspirin can cause nausea, vomiting, tinnitus and
action. The low dose of aspirin required to achieve impaired hearing, which are together referred
antiplatelet action is more easily tolerated with to as salicylism. Hyperventilation also occurs
negligible side effects in most cases. Since the life with high doses of aspirin. Since all NSAIDs
of platelets is approximately 10 days, a subject on share the same mechanism of action, many
antiplatelet therapy requires a period of 7–10 days of their adverse effects are also shared. The
to regain normal platelet function (by the time shared adverse effects of NSAIDs are listed in
new platelets with functional TXA2 replace the Table 11.7.
Topical Ocular Use of NSAIDs these agents should not normally be used in
patients who are sensitive or intolerant to aspirin
Until recently the topical use of glucocorticoids or other NSAIDs. Exacerbation of bronchospasm
has been the mainstay of treatment for ophthalmic in asthmatic patients has been reported with
inflammatory conditions as well as for pre- topical use of NSAIDs.10 Topical NSAIDs have
and postoperative control of inflammation. been reported to cause corneal complications
Corticosteroid therapy provides powerful anti- such as keratitis, epithelial breakdown, erosion,
inflammatory response but is also associated ulceration, perforation and rarely, corneal
with some inherent risks such as increase in melting. 11-13 The exact mechanism for these
intraocular pressure, delayed healing and cataract complications is not clear but a careful monitoring
formation. Availability of topical preparations of for epithelial damage is necessary and any
some NSAIDs has provided an alternative for evidence of same warrants discontinuation of
ocular anti-inflammatory therapy without these topical NSAIDs.
disadvantages. NSAIDs now find important Five topical preparations are currently
uses in ophthalmic practice for prevention of available for ophthalmic use. The preparations
intraoperative miosis, reduction of post-surgical and their recommended uses are given in Table
inflammation and in the treatment of ocular 11.8.
inflammatory conditions.8 Use of topical NSAIDs Several clinical trials to compare the relative
prior to cataract surgery has been reported to efficacy and safety of different topical preparations
facilitate a safer and more efficient surgical did not reveal any marked superiority of any one
procedure (due to a mydriatic effect), reduce agent over another when used during cataract
postoperative pain and inflammation and also or corneal surgery.15-18 Nepafenac, however, has
decrease the risk of post-operative cystoids been reported to be less effective than ketorolac
macular edema. Beneficial effects on pain and in preventing miosis during cataract surgery19 and
inflammation have also been reported in refractive not effective for relieving pain and inflammation
surgery.9 Topical use of NSAIDs is generally safer following keratectomy.20
as compared to their systemic use because of the In addition to their use during ophthalmic
smaller doses and limited absorption into systemic surgery, NSAIDs also find use in the treatment
circulation.Topical application of NSAIDs, may of ocular inflammatory disorders such as
sometimes cause local irritation and discomfort, scleritis, episcleritis and iridocyclitis. Topical
which can affect patient compliance. Further, or systemic NSAIDs may be used as an adjunct
Table 11.7 Adverse effect common to most NSAIDs

Gastrointestinal tract1 Intolerance, irritation, ulceration, hemorrhage, perforation, diarrhea.
Platelets1 Increased bleeding and clotting time, risk of hemorrhage, bruising
Uterus Prolongation of labor
Electrolytes Salt and water retention
Vascular 2
Closure of ductus arteriosus
Kidney Decreased renal function (specially in pre-existing renal or cardiac disease)
CNS Headache, dizziness, vertigo, confusion
Hypersensitivity Asthma, urticaria, angioneurotic edema, asthma3
1
Less with COX-2 selective agents
2
Indomethacin has been used for closure of patent ductus arteriosus
Pre-existing asthma may be worsened due to diversion of arachidonic acid via the LOX pathway for increased leukotriene
3
production.
Table 11.8 Topical ophthalmic NSAIDs and their uses
Drug Indications Comments
Diclofenac* 0.1% Cataract surgery: reduction of pain, Start 24 hours postoperative then
inflammation and photophobia; continue for 2 weeks
Refractive surgery
Start preoperative and then continue
postoperative for 3 days
Nepafenac 0.1% Cataract surgery: reduction of pain and Begin preoperative and then continue for
inflammation upto 2 weeks
Bromfenac 0.09% Cataract surgery: reduction of Begin 24 hours postoperative then

postoperative inflammation continue for 2 weeks
Ketorolac* 0.4%; 0.5% Seasonal allergic conjunctivitis
Cataract surgery: reduction of pain and Begin 24 hours postoperative and then
inflammation continue for 2 weeks
Flurbiprofen 0.03% Refractive surgery: Reduction of pain Postoperative upto 4 days
Cataract surgery: to minimize miosis Begin 2 hours preoperative
*Topical ketorolac and diclofenac have also been used for cystoid macular edema following cataract surgery14
in their management. Their use in inflammation 5. Chandrasekharan NV, Dai H, Roos LT,
associated with infective disorders of the eye has Evanson NK, Tomsik J, Elton TS, et al. COX-3,
been suggested especially since corticosteroid use a cyclooxygenase-1 variant inhibited by
under such conditions is associated with a risk of acetaminophen and other analgesic/antipyretic
exacerbating the infection. drugs: cloning, structure, and expression. Proc
Natl Acad Sci USA. 2002;99(21):13926–31.
6. Butterfield JH. Survey of aspirin administration
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2. Peyman GA, Rahimy MH, Fernandes ML. 1998;48(15):4399–404.
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1994;78(2):138–41. 9. Trattler W. Topical NSAIDs for pain and
3. Klocek MS, Sassani JW, McLaughlin PJ, Zagon inflammation. Review of ophthalmology
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reepithelialization in diabetic rats. J Ocul from: http://www.revophth.com/content/d/
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4. Gifford H. On the treatment of sympathetic 10. Sitenga GL, Ing EB, Van Dellen RG, Younge BR,
ophthalmia by large doses of salicylate of Leavitt JA. Asthma caused by topical application
sodium aspirin or other salicylic compounds. of ketorolac.Ophthalmology. 1996;103(6):
Ophthalmoscope. 1910;8:257–9. 890–2.
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review. Drug saf. 2002;25(4):233–50. 17. Flach AJ, Dolan BJ. Incidence of postoperative
12. Flach AJ. Corneal melts associated with topically posterior opacification following treatment with
applied nonsteroidal anti-inflammatory drugs. diclofenac 0.1% and ketorolac 0.5% ophthalmic
Trans Am Ophthalmol Soc. 2001;99:205–12. solutions: 3-year randomized, double masked,
13. Lin JC, Rapuano CJ, Laibson PR, Eagle RC, prospective clinical investigation. Trans Am
Cohen EJ. Corneal melting associated with use Ophthalmol Soc. 2000;98:101–5.
of topical nonsteroidal anti-inflammatory drugs 18. Narvaez J, Krall P, Tooma TS. Prospective,
after ocular surgery. Arch Ophthalmol. 2000, randomized trial of diclofenac and ketorolac after
118(8):1129–32. refractive surgery. J Refract Surg. 2004;20(1):76–8.
14. Weisz JM, Bressler NM, Bressler SB, Schachat 19. Bucci Jr F, Waterbury L, Amico L. Prostaglandin
AP. Ketorolac treatment of pseudophakic E2 inhibition and aqueous concentration of
cystoids macular edema identified more than 24 ketorolac 0.4% (Acular LS) and nepafenac
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Unlü N, Kasim R, et al. Comparison of the 20. Colin J, Paquette B. Comparison of the analgesic
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ChapteR 12
Corticosteroids
OVERVIEW with “generalized collagen diseases”.1 Later,

ACTH was reported to be effective in various
Corticosteroids have been used for the treatment inflammatory conditions of eyes. One of the
of ocular inflammatory diseases for more earliest works on usage of corticosteroids in
than 60 years. They are the most prescribed ophthalmology was the study of Wood (1950)
pharmacological group in ophthalmology because demonstrating efficacy of ACTH and cortisone
large number of acute ocular diseases are in 14 patients with inflammatory ocular diseases.2
inflammatory in nature such as non-infectious Mann and Markson (1950) showed positive result
conjunctivitis, uveitides, episcleritis, inflamed of ACTH application in patients with uveitis and
pingueculae, chemotoxic keratoconjunctivitis, episcleritis.3
phlyctenular keratoconjunctivitis, contact lens The next important step for progression of
associated red eye, allergic conjunctivitis, anti-inflammatory therapy in ophthalmology
blepharitis, corneal infiltrates, ocular trauma,
was introduction of topical formulations of
recurrent corneal erosions, etc. Though many
aspects of their adverse effects still remain open, cortisone. Their clinical use was accompanied
anti-inflammatory and immunosuppressive by rapidly growing number of indications
actions are valuable therapeutic effects in in 1950’s, including vernal conjunctivitis,
ophthalmic diseases. This chapter describes the episcleritis, scleritis as well as inflammatory
pharmacological aspects of corticosteroids in conditions of the uvea. After introduction of
ophthalmology. prednisone and prednisolone by Schering in
mid-1960s under the brand names Meticorten
HISTORY and Meticortelone, ophthalmologists received a
therapeutic instrument that was 10 time stronger
Tadeusz Reichstein, Edward Calvin Kendall and in its anti-inflammatory action in comparison with
Philip Showalter Hench were awarded the Nobel
cortisone. However, within a few years, a number
Prize for physiology and medicine in 1950 for
of ophthalmic adverse effects, such as cataract
their work on hormones of the adrenal cortex,
which culminated in the isolation of cortisone. The and elevated intraocular pressure, were reported.4
history of corticosteroids in ophthalmic therapy Additionally, it was established, that there is
starts with Elkinton and co-authors (1949), who a close correlation between anti-inflammatory
first applied ACTH therapy in patients with potency of applied corticosteroids and risk of
inflammatory hemorrhagic retinopathy associated ocular hypertension.
PHARMACOLOGY OF Most of the pharmacokinetic studies of topical

CORTICOSTEROIDS corticosteroids have been done in rabbits and the
data obtained from these experiments may not be
Classification suitable to extrapolate in human because of the
anatomical and physiological differences between
The chemical structure of all corticosteroids the rabbit and human eye. Despite these differences,
is ketone based except for loteprednol, which there are similarities between the two eyes allowing
is ester based. The most commonly prescribed extrapolation of data from rabbit to human.
steroids, prednisolone and dexamethasone, are Most topically applied corticosteroids penetrate
ketone-based. Other classification is based on the the eye via cornea. Following a single drop
strength of action and classifies corticosteroids in
topical application, steroids have been detected
two groups of maximum and moderate strength
in measurable quantity in human aqueous humor
steroids (Table 12.1).
within 15–30 minutes.6 Some pharmacokinetic
parameters of topical corticosteroids indicating
Pharmacokinetics rate and extent of corneal permeation are
Topical application of ophthalmic formulations summarized in Table 12.2.7
(drops, ointments) is the most common route Corneal penetration studies conducted in
of administration of corticosteroid to the eye. unanesthetized rabbits have described transfer
Although, the clinical benefits and adverse events through the epithelium as the rate-limiting
associated with systemic corticosteroid use are well step for absorption of hydrophilic compounds,
documented, their basic pharmacokinetics after whereas transfer through the stroma is rate-
topical application is yet to be fully elucidated. limiting for hydrophobic compounds. However,
Table 12.1 Classification of corticosteroids based on the strength of their action5
Generic name Brand name Manufacturer Preparation Contents

Maximum strength (steroids)
Difluprednate 0.05% Durezol Sirion Therapeutics Emulsion 5 mL
Loteprednol etabonate 0.5% Lotemax Bausch and Lomb Suspension 2.5 mL, 5 mL,
10 mL, 15 mL
Prednisolone acetate 1%, Pred Forte, generic Allergan and Suspension 1 mL, 5 mL,
generic 10 mL, 15 mL
Prednisolone sodium Generic Generic Solution 5 mL, 10 mL,
phosphate 1% 15 mL
Rimexolone 1% Vexol Alcon Suspension 5 mL, 10 mL
Moderate strength (steroids)
Fluorometholone acetate 0.1% Flarex and generic Alcon Suspension 5 mL, 10 mL
Fluorometholone alcohol 0.1% FML and generic Allergan Suspension 5 mL, 10 mL,
15 mL
Fluorometholone alcohol 0.1% FML SOP Allergan Ointment 3.5g
Prednisolone acetate 0.12% Pred mild and Allergan Suspension 5 mL, 10 mL
generic
Medrysone 1% HMS (medrysone Allergan Suspension 5 mL, 10 mL
ophthalmic
suspension)
Corticosteroids 173
Table 12.2 Human aqueous humor concentration of corticosteroids following topical and subconjunctival
application (according to Awan7 with modification)
Drug Route Dose Mean peak Time Aqueous Aqueous
(Number aqueous to peak concentration concentration
of drops, concentration concen- at 12 hours at 24 hours
frequency (ng/mL) tration (ng/mL) (ng/mL)
of instilla- (minutes)
tion)
Dexamethasone
Topical (drops) 0.1% (1) 31 90–120 3.1 NA
alcohol
Dexamethasone
– cyclodextrin-
Topical (drops) 0.32% (1) 140 150 NA NA
polymer co-
complex
Dexamethasone
disodium Topical (drops) 0.1% (10) 30.5 55 NA NA
phosphate
Prednisolone
Topical (drops) 1% (1) 669.9 120 99.5 28.4
acetate
Prednisolone
Topical (drops) 1% (1) 1130 30–45 NA NA
acetate
Prednisolone
Topical (drops) 0.5% (1) 25.6 90–240 0 NA
sodium phosphate
Betamethasone
Topical (drops) 0.5% (1) 7.7 90–120 2.5 0.4
phosphate
Fluorometholone
Topical (drops) 0.1% (1) 5.1 31–60 NA NA
alcohol
Clobetasone Topical
0.1% (1) 0.1 810 0.1 NA
butyrate (ointment)
Betamethasone Topical
0.1% (1) 20.3 810 20.3 NA
phosphate (ointment)
Hydrocortisone
Subconjunctival 0.5 mL (1) 214 × 103 10 NA 103 × 103
acetate 2.5%
Dexamethasone
sodium phosphate Subconjunctival 0.5 mL (1) 268 × 103 10 NA 123 × 103
0.4%
very low molecular weight compounds penetrate despite identical concentrations of the same
well through the corneal epithelium and appear steroid. Therefore, it cannot be assumed that
rapidly in aqueous humor. These observations equivalent steroid contents in a formulation
are in accordance with the proposed “pore” assure equivalent efficacy. Based on the duration
model for the penetration of drugs through of action, ophthalmic corticosteroid formulations
the cornea. According to this proposed model, can be placed in the following ascending order:
corneal permeability of drugs depends on both drops → cream → ointment. The rate and extent
the partition coefficient and molecular-weight.7 It of corneal permeation is affected by not only
has also been demonstrated in a rabbit study that the drug’s concentration and its physiological
cornea becomes significantly less permeable with properties but also by several excipients used in the
age, particularly for large hydrophilic compounds. formulation. Therefore, even small modifications
Different topical formulations may show in the composition of formulation can significantly
marked differences in pharmacokinetic behavior affect intraocular drug concentration.
The role of peribulbar injection is limited to Pharmacological Effects
the operating room and to a few other selected
situations where frequent topical medication is not Anti-Inflammatory
suitable. Subconjunctivally injected steroids enter Corticosteroids are potent anti-inflammatory
the eye via sclera. Topical and local administration agents and inhibit inflammatory processes
of steroids appears preferable to systemic admi above the site of action of NSAIDs (Fig. 12.1).
nistration wherever possible. However, the Corticosteroids inhibit the generation of prost
limitations of, and alternatives to, subconjunctival aglandins by producing proteins called lipocortins.
injection should be carefully considered, should Lipocortins exert their effect on the prostaglandin
the possibility of adrenal suppression following cascade by inhibiting phospholipase A2. The major
intensive topical corticosteroid therapy arise in effect is inhibition of migration of inflammatory
children and small adults. The local administration cells (including neutrophils and monocyte-
of ocular corticosteroids enables the use of smaller macrophages) into the site of inflammation. They
doses for equivalent or greater local corticosteroid also inhibit lysosomal enzyme release. Inhibition
concentration, more target-specific drug application of prostaglandin E 2 may be the dominant
and reduced risk of systemic adverse events. mechanism for their anti-inflammatory effects.
There is also evidence for anti-interleukin-1 and
Mechanism of Action anti-TNFa effects.
The pharmacological effects of corticosteroids
are mediated through the glucocorticoid receptor, Immunosuppression
which is located in the cytoplasm. Due to the Corticosteroids suppress the cell-mediated
ubiquitous nature of the glucocorticoid receptor, immunity. They act by inhibiting genes that
corticosteroids act on a wide variety of cell types. code for the cytokines such as interleukin-2 and
Glucocorticoid receptor is expressed in almost all interferon-γ, the most important of which is IL-2.
tissues and cells, and the effects, both beneficial Reduced cytokine production prevents the T cell
and unwanted, of corticosteroids are mediated proliferation.
through reversible binding to this receptor. After Corticosteroids also suppress the humoral
binding to the receptor, the drug-receptor complex immunity, causing B cells to express smaller
translocates into the nucleus, binds to DNA, and amounts of IL-2 and of IL-2 receptors. This
hence activates or represses gene transcription diminishes both B cell clone expansion and
through different mechanisms. The complexes antibody synthesis. The diminished amounts of
may induce the transcription of mRNA leading IL-2 also cause fewer T lymphocyte cells to be
to synthesis of new proteins (transactivation). activated.
Such proteins include lipocortin, a protein known
to inhibit phospholipase A2 and, thereby block
Therapeutic Uses
the synthesis of prostaglandins and leukotrienes.
Glucocorticoids also inhibit the production Corticosteroids remain the first line treatment in
of other mediators including arachidonic acid non-infectious ocular inflammation and can be
metabolites such as cytokines, the interleukins, administered topically, periocularly, intravitreally
adhesion molecules, and enzymes such as and systemically. Corticosteroids do not appear to
collagenase. Transactivation was also found have specific effects but exert a broad spectrum
to be associated with several side-effects of of anti-inflammatory activity. They are more
corticosteroids. The transrepression, repression effective in acute than in chronic inflammatory
of transcription factors such as nuclear factor-kB conditions. Some aspects of corticosteroid-
and activator protein-1, seems to be responsible induced effects are of particular importance for
for the anti-inflammatory effect.8-10 the treatment of ocular diseases. For example, the
Corticosteroids 175
Figure 12.1 Prostaglandin synthesis inhibition. NSAIDs–Non-steroidal

anti-inflammatory drugs, PGG2–prostaglandin G2, PGH2–prostaglandin H2,
PGE2–prostaglandin E2, PGFa2–prostaglandin Fa2; (+) stimulating effect;
(–) inhibiting effect
reduction of fibrinoid exudation and inhibition of anterior segment of the globe as well as in ocular
corneal scar formation are important to prevent allergic conditions (Table 12.3). Fluorometholone
secondary complications of ocular inflammation (0.1%), medrysone, or prednisolone (0.125%)
and to maintain corneal transparency. If a long- may be preferred for long-term treatment because
term anti-inflammatory effect is needed, less they are least likely to increase intraocular
potent corticosteroids should be slowly replaced pressure.
because of the potential side-effects of long- The ocular surface may exhibit a wide variety
term use, such as cataract, glaucoma and local of immunologic responses that may result in
immunosuppression. conjunctival and corneal inflammation and may
in certain instances be the specific and only target
Ocular Indications for Topical affected by certain autoimmune diseases. Topical
Corticosteroid Use steroids are very effective in treating signs and
symptoms of allergic and autoimmune ocular
Topical corticosteroids are indicated in the diseases.
treatment of corticosteroid-responsive allergic
and inflammatory conditions of the palpebral and Ocular Indications for Periocular
bulbar conjunctiva, cornea and anterior segment
diseases (Table 12.3). Topical corticosteroids
Corticosteroid Use
suppress all aspects of the inflammatory process Periocular administration is used when more
such as edema, fibrin deposition, capillary dilation, posterior effects are needed or if the patient is
leukocyte migration, capillary proliferation, non-compliant.11 Several techniques have been
deposition of collagen, scar formation, and advocated for the periocular application of
fibroblastic proliferation. Topical corticosteroids corticosteroids, including subconjuctival, sub-
are effective in acute inflammatory conditions Tenon’s, transeptal, orbital floor, and retrobulbar
of the conjunctiva, sclera, cornea, lids, iris, and injections.11
Table 12.3 Ocular indications for topical corticosteroid use
Pathology Clinical Use

localization
Eyelids Blepharitis, chalazia, dermatitis, burns
Conjunctiva Conjunctivitis (various types), mucocutaneous lesions, burns
Cornea Edema, graft rejection, rosacea keratitis, dry eye syndrome, interstitial keratitis, herpes simplex
(stromal) keratitis, herpes zoster keratitis, post-Herpes zoster neuralgia, infiltrates, marginal
ulcers, burns
Uvea Iridocyclitis, uveitis, traumatic hyphema, sympathetic ophthalmia
Sclera Episcleritis, scleritis
Retina Vasculitis, chorioretinitis
Optic nerve Neuritis, temporal arteritis
Orbit Endophthalmitis, pseudotumor cerebri, Grave’s ophthalmopathy
Ocular Indications for Intraocular injections or when the uveitis is associated with
(Intravitreal) Corticosteroid Use systemic disease. A concerning ocular side-
effect of corticosteroids is ocular hypertension
Intraocular injections of corticosteroid can also be especially with long-term use (more than three
used to deliver a high concentration of corticosteroids, months). Systemically administered steroids
to treat inflammation involving both anterior are used less often in ocular diseases. Ocular
and posterior segments.11 Often the intraocular indications for oral or injectable steroids include
concentrations of topically applied steroids fail to the following:
achieve therapeutic levels and, therefore, intraocular
Uveitis not responding to topical therapy
injections may be of benefit in certain ocular
Posterior uveitis and/or chorioretinitis
disorders including diabetic macular edema, cystoid
Orbital pseudotumor
macular edema, age-related macular degeneration,
Acute ocular allergic response not responding
retinal vascular occlusion and uveitis.12 Intravitreal
triamcinolone acetonide provides an effective short- to topical therapy
term treatment for persistent macular edema and Scleritis—subconjunctival injections are
may be a useful adjunctive treatment for choroidal contraindicated
neovascularization. The side-effect profile of Temporal arteritis/arteritic anterior ischemic
intravitreal corticosteroids is significant and includes optic neuropathy

increase in corticosteroid-induced intraocular Optic neuritis
pressure. With long-term studies, the rate of posterior Severe burns

subcapsular cataract formation is higher, and there Underlying autoimmune diseases (collagen-
is a small but potential risk of endophthalmitis.13 vascular disorders).
Recently, sustained-release intraocular corticosteroid
implants are emerging as potential treatments for
macular edema due to uveitis, diabetic macular Adverse Effects
edema or retinal vascular occlusion.12, 14-16
Corticosteroids are one of the most potent and
Ocular Indications for Systemically effective drug classes available in the treatment of
ocular inflammation. However, they can produce
Administered Corticosteroid
variety of adverse ocular and systemic effects.
Systemic steroids can be used to treat ocular Corticosteroid-induced ocular hypertension
inflammation recalcitrant to topical and periocular- and glaucoma are significant risks of local and
Corticosteroids 177
systemic administration. Posterior subcapsular Contraindications
cataract, observed after about 4 months of
topical corticosteroids use, is supposed to be Corticosteroids are contraindicated in patients with
due to covalent binding of corticosteroid to lens viral infections, fulminant bacterial infections,
proteins with subsequent oxidation. Inappropriate fungal infections, injuries and glaucoma.
use of topical corticosteroids in the presence of
corneal infections also continues to be a cause Corticosteroids used in Ophthalmic
of ocular morbidity. Corticosteroids may cause Diseases
retardation of corneal epithelialization, i.e.
Prednisolone Acetate 1% as Pred Forte (Allergan)
the time required for epithelial regeneration is
is a highly prescribed topical steroid. Prednisolone
increased in eyes treated with steroids. Effects
acetate is a suspension and is, therefore, optimally
on collagen synthesis and fibroblast activity
suited for penetrating the cornea and the anterior
have been proposed as a possible mechanism.
chamber. This makes it effective for treating
Paradoxically, the topical use of dexamethasone
anterior chamber inflammation and it remains
or prednisolone can lead to acute inflammation
the drug of choice in treating anterior uveitis.
of the anterior segment of the eye (corticosteroid Prednisolone acetate 1% is used for moderate
uveitis). The incidence is higher in the black to severe forms of ocular inflammation such
population (5.4%) than in the white population as episcleritis, iritis, inflammatory keratitis,
(0.5%). Corticosteroids increase susceptibility to chemical or thermal burns of the cornea.
microbial infections. Prolonged use may aid in Prednisolone acetate is available in 1% and
the establishment of secondary ocular infections 0.125% concentrations.
from fungi and viruses.
Prednisolone sodium phosphate 1% solution
Other risks of locally administered ophthalmic
as Inflamase Forte (Novartis) is a commonly
corticosteroids include: epithelial toxicity,
prescribed steroid solution. It penetrates less
crystalline keratopathy, decreased wound strength, readily into the aqueous and is not as effective
orbital fat atrophy, ptosis, limitation of ocular as suspensions in treating uveal inflammation.
movement, inadvertent intraocular injection, and It is, however, an excellent choice for treating
reduction in endogenous cortisol. moderate to severe inflammatory disorders of
Almost all the side-effects—most notably the ocular surface. It is used for the treatment
cataracts and increased intraocular pressure of episcleritis, acute allergic inflammation,
– are minimal or absent with the ester-based superior limbic keratoconjunctivitis, traumatic
formulation, and only occasionally are inflammation and other advanced ocular surface
problematic even with the ketone formulation. diseases.
The key to these differences is that the human Dexamethasone (as dexamethasone alcohol
body possesses abundant esterases, but has 0.1% and dexamethasone disodium phosphate
no ketones. Ketone-based steroids such as 0.1%) is more potent and longer acting, but
prednisolone and dexamethasone linger in its corneal penetration is less than that of
tissues, which renders good therapeutic effect prednisolone acetate. Dexamethasone achieves its
but concurrently places patients at risk for peak concentration in aqueous humour between
undesirable side-effects such as posterior 91 and 120 minutes following instillation (mean
subcapsular cataracts and increased IOP. concentration, 31 ng/mL) and is still detectable
In contrast, ester-based steroids provide a in the aqueous 12 hours after instillation.17 The
potent anti-inflammatory effect and as they dexamethasone has the highest propensity for
undergo enzymatic degradation, the potential for increasing intraocular pressure, particularly in
development of adverse side-effects minimizes. the long term. Thus, there is little reason to use
dexamethasone monotherapy. However, for short- inflammations requiring long-term (beyond 3 to
term use in combination products, it is effective in 4 weeks) therapy. Fluorometholone alcohol is
treating moderate inflammation. Dexamethasone available in both 0.1% and 0.25% suspensions
(Maxidex® and Ak-Dex, Dexasol) is approved by and 0.1% ointment. The 0.25% suspension offers
FDA for the treatment of inflammatory conditions little, if any, clinical advantage over the 0.1%, and
of the palpebral and bulbar conjunctiva, cornea, is rarely used. Fluorometholone alcohol’s value in
and anterior segment of the globe and corneal chronic care lies in its reduced tendency to cause
injury. Dexamethasone (Ozurdex™) is FDA- secondary IOP increase.
approved for treatment of macular edema Fluorometholone acetate is a more potent form
following branch retinal vein occlusion or central of fluorometholone, and is used for moderate to
retinal vein occlusion. moderately severe conditions. It has relatively
Rimexolone 1% suspension as Vexol (Alcon) low IOP-sparing effect. The peak aqueous humor
has similar anti-inflammatory activity level of fluorometholone is 5.1 ng/mL between 31
as corticosteroids such as 1% prednisolone and 60 minutes, and significant concentrations
acetate. It is used for the treatment of uveitis of fluorometholone (mean level 4.3 ng/mL)
and post-surgical inflammation. A double-blind, were detected between 181 and 240 minutes.21
randomized, crossover study of corticosteroid This drug does not have quite the clinical
responders compared the effects of 1% efficacy of 1% prednisolone acetate, yet can be
rimexolone on intraocular pressure with those useful in a wide array of ocular inflammatory
of 1% prednisolone and 0.1% fluorometholone. conditions. As acetate ophthalmic suspension,
The results suggested that the intraocular pressure fluorometholone (Flarex®) is FDA-approved for
elevating potential was comparable to that of use in the treatment of inflammatory conditions
fluorometholone.18, 19 Its safety profile is similar of the palpebral and bulbar conjunctiva, cornea,
to the fluorometholones, which gives it an and anterior segment of the eye.
enhanced margin of safety. Rimexolone is used Loteprednol etabonate is ester-based class of
for the treatment of anterior uveitis and also is steroids. It is an entirely new generation of
the first FDA-approved ophthalmic product for corticosteroids using an ester base.22 Loteprednol
post-operative care of cataract surgery patients. is structurally similar to other corticosteroids.
However, the ketone group at position number
Betamethasone is potent and long-acting, but does
20 is absent. It is highly lipid soluble, which
not penetrate well. Betamethasone concentration
enhances its penetration into cells. Loteprednol
is highest during 91–120 minutes following
is synthesized through structural modifications
topical administration (mean peak concentration
of prednisolone-related compounds so that it
7.7 ng/mL). At 12 hours post-instillation, the
undergoes a predictable transformation to an
mean concentration of betamethasone is 2.5 ng/
mL, and detectable levels are still measurable in inactive metabolite. Based upon in vivo and in
the aqueous humor 24 hours after application.20 vitro preclinical metabolism studies, loteprednol
undergoes extensive metabolism to inactive
Steroid-induced cataracts and glaucoma have
carboxylic acid metabolites. Primary site of
been reported, most often in patients receiving
deactivation of the topically applied drug is
betamethasone eyedrops. It is available as eyedrop
the corneal tissue. A substantial amount of
solution.
metabolites were also detected in the iris, although
Fluorometholone alcohol is moderate-strength these were lower than in the cornea. The amount
ophthalmic suspension. It is used to treat mild to of drug and metabolites in the aqueous humor was
moderate ocular surface inflammatory conditions. low.23 Loteprednol is indicated for the treatment
It is also a useful drug in treating chronic of inflammation of the eye due to allergies, as
Corticosteroids 179
well as chronic forms of keratitis (adenoviral and corticosteroids. It is available as ophthalmic
Thygeson’s keratitis), vernal keratoconjunctivitis, suspension. Medrysone was historically marketed
pingueculitis, and episcleritis. The drug renders to treat ocular allergies, but newer, better choices
a potent anti-inflammatory effect and is have made it obsolete.
subsequently broken down into inert components Triamcinolone acetonide (Intravitreal) is used
by resident tissue esterases. It is available in to deliver a high concentration of corticosteroids
both a 0.5% suspension (Lotemax™) and a to the anterior and posterior segments of eye for
0.2% suspension (Alrex). Lotemax™ is food the treatment of inflammatory conditions. Recent
and drug administration (FDA) approved for studies have reported increasing use of intravitreal
treatment of inflammatory conditions of the triamcinolone acetonide in the treatment of
palpebral and bulbar conjunctiva, cornea, and other intraocular proliferative, edematous and
anterior segment of the globe, treatment of post- neovascular diseases.12,14-16 The complications
operative inflammation following ocular surgery. of intravitreal triamcinolone therapy include:
Lotemax™ and Alrex are approved for treatment secondary ocular hypertension, medically
of ocular allergy, including dry eye. uncontrollable high intraocular pressure, posterior
Clobetasone butyrate (0.1%) is a topical subcapsular and nuclear cataract and post-
corticosteroid ophthalmic preparation for the operative infectious endophthalmitis. Intravitreal
treatment of ocular inflammation. Clobetasone triamcinolone injection can be combined
butyrate had significantly less effect on raising with other intraocular surgeries, including
intraocular pressure than dexamethasone. cataract surgery, particularly in eyes with iris
Difluprednate 0.05% ophthalmic emulsion neovascularization.25 In non-vitrectomized eyes,
(Sirion Therapeutics) is the first “emulsion” the duration of the effect and side-effects of a
formulation of corticosteroid to come to the single intravitreal injection of triamcinolone
market. Unlike a suspension, an emulsion does is about 6–9 months for a dosage of about 20
not require shaking because emulsions maintain mg, and about 2–4 months for a dosage of 4
homogenous molecular distribution within mg.25 Triamcinolone acetonide (Triesence™) is
the vehicle. It is a difluorinated derivative of approved by FDA for the treatment of sympathetic
prednisolone and, therefore, another ketone- ophthalmia, temporal arteritis, uveitis, and ocular
based corticosteroid, similar to dexamethasone. inflammatory conditions unresponsive to topical
The emulsion vehicle allows for enhanced ocular corticosteroids.
surface contact time, thereby allowing less
frequent instillation, as compared to non-emulsion Conclusion
delivery systems. Durezol (Durezol™) is FDA-
approved specifically for the “management of Corticosteroids are some of the most potent
inflammation and pain after intraocular surgery”.24 and effective drugs for the treatment of ocular
Medrysone is indicated for the treatment of inflammation. However, despite the continuing
allergic conjunctivitis, vernal conjunctivitis, development of techniques and vehicles for
episcleritis, and epinephrine sensitivity. Adverse local administration of corticosteroids, both
reactions include occasional transient stinging systemic and ocular adverse events continue to be
and burning on instillation. Increased intraocular reported with ocular corticosteroid preparations.
pressure and posterior subcapsular cataract Although non-steroidal anti-inflammatory drugs
formation have been reported rarely with the have been shown to challenge the therapeutic
use of medrysone. Systemic absorption and efficacy of corticosteroids in a number of
side-effects may result with the use of topical ophthalmic conditions without the associated risk
of elevated intraocular pressure, decreased wound 11. Bodh SA, Kumar V, Raina UK, Ghosh B, Thakar
strength or predisposition to infection, topical M. Inflammatory glaucoma. Oman J Ophthalmol.
corticosteroids remain a fundamental component 2011;4(1):3–9.
of the ophthalmic therapeutic strategy. 12. Kiernan DF, Mieler WF. The use of intraocular
corticosteroids. Expert Opin Pharmacother.
2009;10(15):2511–25.
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ChapteR 13
Drugs Used in Ocular Allergy
OVERVIEW are discussed here mainly for comparison with

H 1 receptor blockers. They do not have any
Allergies frequently affect ocular structures, most uses specific to the eye. Mast cell stabilizers
commonly the conjunctivae. Allergic manifestations which inhibit release of histamine and other
in the form of conjunctival congestion, burning, inflammatory mediators during allergic response
itching, increased secretions and swelling of are discussed as are drugs with combined
eyelids may be triggered by localized contact of antihistamine and mast cell stabilizing effects.
environmental antigens with the eye surface or Ocular decongestants that are clinically useful
may form a part of a systemic response to some belong to the group of sympathomimetics, which
exogenous or intrinsic allergens. Sympathomimetic reduce hyperemia by virtue of their vasoconstrictor
drugs with vasoconstrictor actions are effective effects. Only the role of sympathomimetic drugs
in reducing conjunctival congestion and reducing as vasoconstrictors and decongestants is discussed
secretions. Since histamine has a well established role in this chapter and their other ocular uses have not
in acute allergic disorders, drugs which interfere with been included.
either the release of histamine from the mast cells by
inhibiting degranulation, or those which block the H1
histamine receptors are useful in the management of HISTAMINE
allergic disorders. Although both, sympathomimetic
decongestants as well as antihistaminic drugs may be Histamine is a biologically active endogenous
used by the systemic route, for ophthalmic purposes amine, which serves complex physiological as
local instillation is the commonly employed method. well as pathological functions through multiple
Several ocular preparations containing antihistaminic receptors. It occurs both, as a neurotransmitter
agents, decongestants or their combinations are in neurons originating mainly from the posterior
available. hypothalamus 1,2 and as an autacoid released
Some fraction of the drugs administered locally by tissues. The central role of histamine
topically to the eye is likely to get absorbed into in initiating the allergic response has been
the systemic circulation via nasolacrimal drainage well established following its isolation from
and subsequent swallowing. However, systemic mammalian tissues over a hundred years back.
adverse effects following topical use are much Sir Henry Dale demonstrated that histamine
smaller in magnitude as compared to systemic application could mimic a type 1 (immediate
administration. hypersensitivity) anaphylactic response in
This chapter includes a brief discussion on sensitized tissue both in vivo and in vitro.
the role of mast cells and histamine in allergic Locally applied histamine has been shown to
disorders. Antagonists of histamine H2 receptors produce swelling, redness and edema while its
Drugs Used in Ocular Allergy 183
administration intravenously produces symptoms Organ System Effects of Histamine
identical to systemic anaphylaxis.
The discovery of histamine in mast cells led Among the important physiologic functions of
to further elucidation of its biological activity histamine in humans is its role in secretion of gastric
and role in antigen-antibody mediated allergic acid and as a neurotransmitter/neuromodulator. A
reactions. Histamine is synthesized from histidine role of histamine in chemotaxis has also been
by enzymatic action of histidine decarboxylase. suggested. Histamine exerts its physiologic and
It is found in mast cells and basophils in almost pharmacologic effects through specific cell surface
all tissues with particularly high concentrations G-protein coupled receptors belonging to the seven
in lungs, skin and the gastrointestinal tract. In membrane-spanning receptor superfamily. Four
addition, it is also present in ‘histaminocytes’ distinct histamine receptors, designated H1-H4 have
in the stomach and in histaminergic neurons been cloned. While H1 receptor has been widely
in the brain. Formed histamine in mast cells accepted to play a major role in allergic diseases,
and basophils is stored in intracellular granules all four receptor types have been implicated in the
complexed with a protein and heparin and is inflammatory response.3 Important characteristics
released by exocytosis during antigen-antibody of histamine receptors are summarized in Table
reactions triggering inflammatory responses. The 13.1 and the pharmacological effects of histamine
complement system activated during the antigen- on tissue and organ system are given in Table 13.2.
antibody reaction acts on specific cell surface “Triple response”: Experimental intradermal
receptors to trigger an increase in cytosolic injection of histamine produces a characteristic
calcium, which then causes release of histamine response manifesting as a red spot, a raised wheal
in a fashion similar to other secretory processes. (edema) and surrounding reddish flare. Itching is
Histamine can also be released from the mast also seen in and around the site of injection. These
cells directly by certain chemicals and drugs responses result from the effects of histamine
such as morphine and d-tubocurarine as also by on the vascular smooth muscle (redness), the
mechanical injury to mast cells. Contrary to this, vascular endothelium (edema due to increased
agents such as β-adrenoceptor agonists, which permeability) and the sensory nerve endings
increase intracellular cAMP formation inhibit the (itching due to direct effects and reddish flare
release of histamine. Two enzymes, histaminase surrounding the wheal due to an axon reflex).
and N-methyltransferase are responsible for the This response is almost identical to that seen after
breakdown of released histamine. insect bites or on local contact with allergens.
Table 13.1 Subtypes of histamine receptors4-8
Receptor Major presence Agonist Classical effect Antagonist

H1 Smooth muscles, Histamine, Smooth muscle contraction Mepyramine
endothelium, brain Methylhistaprodifen (except blood vessels)
H2 Gastric mucosa, Histamine Stimulation of gastric Cimetidine
myocardium, mast Dimaprit secretion; cardiac stimulation Ranitidine
cells, brain Amthamine
H3 Brain, myenteric Histamine Presynaptic inhibition of the Thioperamide
plexus R-alpha methylhistamine release of neurotransmitters
H4 Eosinophils, Histamine Chemotaxis; may play a role JNJ7777120
neutrophils, T-cells Clobenpropit, Clozapine in inflammation and allergy Thioperamide
Table 13.2 Tissue and organ system effects of histamine
Tissue/organ system Major action Receptor type Manifestations

Nervous system
Sensory nerves Stimulation H1 Urticaria, reaction to insect bites
and stings
Presynaptic action Inhibition of the release H3 ↓ release of Ach1, peptide and
of neurotransmitter amine transmitters
Cardiovascular system
Vascular smooth muscle Relaxation H1 and H22 ↓ systolic and diastolic BP
Vascular endothelium Increased permeability H1 Edema, urticaria
Heart Stimulation H2 ↑ HR (direct) and reflex3

Respiratory system
Bronchial smooth muscle Contraction H1 Asthmatic attacks
Gastrointestinal system
Smooth muscle Contraction H1 Diarrhea
Gastric secretions increased H2 ↑ gastric acid, pepsin
1
Acetylcholine;
2
H2 receptors also mediate dilatation at higher doses;
3
Due to vasodilatation and fall in BP.
ANTIALLERGIC DRUGS nally, corticosteroids may also sometimes

be employed for their antiallergic and anti-
Since allergic disorders of the eye, especially inflammatory actions.
those affecting the conjunctiva, are most often due
to environmental antigens, a modification of the Antihistamines
patients environment or limiting his exposure to the
antigens may, at least theoretically, be attempted These are compounds, which competitively
to mitigate the symptoms. However, this may not block histamine receptors. H1 receptor blockers
be practically feasible or effective in many cases, have been used for a long time as antiallergic
thus requiring the use of antiallergic medication. agents. There are many members in this class
Systemic administration of antiallergic drugs may and are generally classified into two generations:
be required for some cases, such as those arising 1st generation (older) agents, which block H1
as a consequence of constitutional disorders or receptors and also manifest moderate to marked
affecting deeper structures, but in most cases sedation as a side effect as well as other CNS
of allergic conjunctivitis local application is actions; 2nd generation agents, which do not
sufficient to control the symptoms with minimum readily cross into the CNS and hence have
liability for systemic adverse effects. minimal sedating effects. The histamine H 2
Antiallergic drugs that are in clinical use can receptor blockers are used primarily for reducing
be categorized in three groups viz: gastric acid secretion but some use for these has
i. Antihistamines: competitive blockers of also been suggested in allergic disorders.
histamine receptors;
ii. Mast cell stabilizers: which prevent mast cell H1 Receptor Blockers
degranulation and
iii. Dual action drugs: which possess combined All the H1 receptor antagonists have an amine
properties of the above two groups. Additio structure with attached chemical groups that
differentiate them into various subgroups nasopaharyngeal and oropharyngeal mucosa
(Table 13.3). All of these competitively block following drainage via the nasolacrimal duct.
histamine H1 receptors on the effector sites thus Other Pharmacological Effects: Apart from their
preventing histamine from initiating an action. antiallergic effects, H1 receptor antagonists also
They have little effect on H2 or H3 receptors. produce several other pharmacological effects
The binding of H 1 receptor antagonists is many of which are not related to blockade of H1
reversible thus their efficacy is dependent on receptors.
their concentration relative to that of the local
Sedation: This is seen mostly with the 1st
histamine levels at the site. In addition, the
generation H1 receptor antagonists, although,
1st generation agents are also likely to block
the extent varies among different classes (Table
other autonomic receptors. This might explain
13.3). Toxic doses may result in marked CNS
some of their other effects such as antiemetic,
excitation leading to convulsions. Children may
anticholinergic and antiparkinsonian.
occasionally display excitement even with normal
Pharmacokinetics: H1 receptor antagonists are doses. 2nd generation members are relatively
rapidly absorbed after oral administration and free of sedative effects and are thus preferred for
are widely distributed throughout the body. Peak daytime use.
concentrations following oral administration are
achieved within 1–2 hours. Symptomatic relief Anticholinergic effects: As shown in Table 13.3
may begin to appear within half an hour and below, many 1st generation agents also possess
lasts up to 4–6 hours with most agents. Duration antimuscarinic actions. This may result in drying
of action is longer with many 2nd generation of mucosal secretions (beneficial for rhinorrhea),
agents and may be up to 12 hours or more. The 1st dry mouth, urinary retention and blurring of vision.
generation agents cross the blood-brain barrier to Antiemetic effects: Some 1st generation H 1
enter the brain while 2nd generation agents do not receptor antagonists, mainly belonging to
readily do so, which explains the lack of sedating phenothiazine group are useful as antiemetics,
effects with the latter. 2nd generation agents are while the piperazines have been found to be
less lipid soluble as well as they are substrates for effective for prophylaxis of motion sickness.
P-glycoprotein reverse transporter in the blood- Antiparkinsonian effects: Diphenhydramine
brain barrier, both of which limit their entry into
shows significant inhibition of extrapyramidal
the brain. These agents are mostly metabolized in
effects. This may be related to its marked
the liver by the hepatic microsomal cytochrome
anticholinergic activity. It is useful for controlling
P450 enzymes and metabolites are excreted
antipsychotic induced extrapyramidal effects as
in the urine within 24 hours. Metabolites of
well as for adjuvant therapy for some cases of
some agents also retain activity and active
Parkinson’s disease.
metabolites of some like hydroxyzine, terfenadine
and loratidine (cetirizine, fexofenadine and Other miscellaneous effects: Phenothiazine H1
desloratidine, respectively) are themselves used receptor blockers also possess some ά-adrenergic
as antihistaminc drugs. receptor blocking action and may result in
H 1 receptor antagonists that are available orthostatic hypotension in some individuals.
for topical ophthalmic use are formulated in a Local anesthetic activity is present in many 1st
suitable water-soluble form (such as maleate generation H1 blockers due to a blocking action
or phosphate). Following topical application, on sodium channels in a fashion similar to that
they distribute in the preocular tear film and of lidocaine. However, they are seldom used for
also penetrate into the conjunctival layer and local anesthetic purpose. Cyproheptadine also
corneal stroma. Systemic absorption of such exhibits strong serotonin receptor blocking action
topically applied drugs occurs primarily through and some of its pharmacological effects such as on
Table 13.3 Subclasses of H1 antihistaminic drugs
Class Members Antimuscarinic activity Comment
First generation
Ethylenediamines Antazoline1 Moderate sedative and GIT side-
Tripelennamine Mild effects
Pyrilamine1
Ethanolamines Diphenhydramine Significant antimuscarinic and
Clemastine Marked sedative side-effects
Dimenhydrinate
Carbinoxamine
Doxylamine
Alkylamines Pheniramine1 Mild sedation; rarely CNS stimulation
Chlorpheniramine Mild
Brompheniramine
Triprolidine
Phenothiazines Promethazine Marked sedative and antimuscarinic
Trimeprazine Marked effects; used as antiemetics
Methdilazine
Piperazines Hydroxyzine Moderate to marked sedation;
Meclizine cyclizine and meclizine useful for
Cyclizine – motion sickness; hydroxyzine used
Buclizine for sedation and as antiemetic
Piperidines Azatadine Mild Moderate sedation
Cyproheptadine2
Second generation
Piperidines Fexofenadine – Relatively non-sedating
Loratidine
Desloratidine
Piperazines Cetirizine – Relatively non-sedating
1
Ophthalmic preparations;
2
Also possesses antiserotonergic activity; useful for controlling serotonin syndrome; is sometimes also used as appetite stimulant
appetite may be related to this action. Cetirizine with benign prostatic hyperplasia in whom
also inhibits mast cell release of histamine and they can cause acute urinary retention. Marked
other mediators and this may be an additional antimuscarinic effects, typically resembling
mechanism for its antiallergic actions. atropine overdose, are usually seen with high
Adverse Effects: The most commonly encountered or toxic doses of drugs, which have significant
adverse effects with H1 receptor antagonists are muscarinic receptor blocking activity (Table
sedation and antimuscarinic effects, which are 13.3). Postural hypotension can occasionally
described above. Sedation is specially a problem result following use of drugs, which have alpha
with some of the 1st generation agents and these adrenergic receptor blocking activity. The 2nd
are best avoided for daytime use and in persons generation antihistaminic agents are relatively
working with machinery or driving. As mentioned well-tolerated and are devoid of troublesome
above, paradoxical excitation and convulsions side-effects. However, earlier members of this
may occur in children. Antimuscarinic adverse group viz. astemizole and terfenadine were found
effects are usually mild in normal individuals but to induce cardiac arrhythmias and have now gone
might be troublesome in the elderly or patients out of use.
Interactions: Since most H1 receptor antagonists H1 Receptor Blockers for Topical Ocular Use:
utilize CYP enzymes, inhibition of these Of the older H1 receptor antagonists only three
enzymes by other concomitant medications – antazoline phosphate (0.5%), pheniramine
is likely to increase the circulating levels of maleate (0.3 %) and pyrilamine maleate (0.1%)
the antihistaminic agent. This was typically –are available for ocular use and these are
illustrated by the interaction between, the now available in over-the-counter preparations
withdrawn 2nd generation H1 blocker, terfenadine mostly in combination with sympathomimetic,
and the antifungal drug ketoconazole. The latter ocular decongestants. Some newer H1 receptor
inhibits metabolism by CYP3A4 and increases antagonists have also been developed for
the circulating concentrations of the former topical ocular use. These include levocabastine
resulting in an increased incidence of cardiac hydrochloride (0.05%) olopatadine (0.1%), and
arrhythmias. Other antimicrobial agents like the emedastine (0.05%). These have been found to
macrolide antibiotics (e.g. erythromycin) also be effective in controlling itching and hyperemia
inhibit CYP3A4 and thus can cause an increase in allergic conjunctivitis. In addition, there are
in circulating levels of antihistaminic drugs. dual action agents with combined antihistaminic
1st generation agents, which have marked and mast cell stabilizing activities. These are
sedative effects can potentiate the effects of other discussed below.
CNS depressants.
Use of H1 Antihistaminic Drugs for Ophthalmic H2 Receptor Blockers
Allergy: There appears to be no strong justification The main motivation for development of H 2
for systemic use of antihistaminic drugs for receptor selective antagonists was to target the
ocular allergies since i) ocular allergy is mostly stimulatory action of histamine on gastric acid
a local condition ii) topical administration of secretion. The first two compounds, burimamide
antiallergic drugs achieves higher concentrations and metiamide that displayed selective H 2
at the target site more quickly thus resulting in receptor antagonism, however, were later found
faster onset of relief and iii) the total dose of the to be toxic and did not come into clinical use. The
drug required to be administered for achieving first drug of this class that was put to widespread
the desired concentration at the target site is clinical use in peptic ulcer disease was cimetidine.
much lower as compared to that which would be Several congeners have since been developed
required by systemic route. Thus, even allowing and include ranitidine and famotidine, which are
for significant absorption into the systemic one of the most widely prescribed drugs world
circulation, the incidence and intensity of adverse over. There use largely remains confined to the
effects like sedation is likely to be lower with inhibition of gastric acid secretion in peptic
topical administration of H1 receptor blockers. ulcer disease, gastro-oesophageal-reflux disease
The second generation H1 receptor antagonists (GORD) and in hospitalized patients for control
have a lower risk for sedation and anticholinergic of stress-induced ulceration of the gastric mucosa.
adverse effects and may be used by systemic route H 2 receptor antagonists are not used in
for alleviating itching, swelling and hyperemia ophthalmic disorders. However, histamine
without major systemic side-effects. However, induced vasodilatation involves both H1 and H2
topical application of olopatadine (H1 antagonist receptors (Table 13.2), hence there appears to
and mast cell stabilizer) was found to be more be a theoretical basis for the use of H2 receptor
efficacious than one of the most effective systemic blockers in combination with H1 antihistaminic
antihistaminic agents, loratidine, in experimental agents for additional benefits in relation to control
allergen induced conjunctivitis.9 of hyperemia that is associated with allergic
conjunctivitis. Combined use of cimetidine (for gastrointestinal route (oral capsules are used for
which an ophthalmic formulation is available) local action within the gut for gastrointestinal
with H1 receptor blocker pyrilamine, has been allergies) and is not subject to metabolic
shown to reduce the conjunctival hyperemia transformation. For both asthma and ocular
produced by local histamine challenge. 10 allergies, it has to be administered topically, i.e.
Although, currently there is no ophthalmic use by inhalation and as eyedrops respectively. Less
of H2 receptor antagonists, it is likely that they than 10% is absorbed into the systemic circulation
may find a place in the treatment of ophthalmic when chromoglycate is given by inhalation and
allergies. is almost completely eliminated within 24 hours
mostly in unchanged form.
Mast Cell Stabilizers For ocular use a water soluble form of sodium
chromoglycate is available as eyedrops (4%
IgE antibodies develop on first exposure to an solution). Pharmacokinetic details following
environmental antigen, which then becomes topical ophthalmic use in humans are not available.
attached to the surface of the mast cells and However, it is well distributed in the surface
basophils (known as sensitization). On subsequent tear film and also penetrates the conjunctival
contact with the same allergen IgE antibodies on epithelium and substantia propria. Systemic
the surface of the sensitized mast cells interact absorption following repeated instillation is
with the antigen to trigger an influx of calcium negligible (less than 0.1% in rabbits) and this
into the mast cells with consequent degranulation occurs via drainage into the oropharynx and
and release of histamine and some other mediators nasopharynx through the nasolacrimal duct.
of inflammatory response. Histamine receptor
Mechanism of Action: Cromolyn prevents the
blockers can prevent histamine from acting on the
release of histamine and slow reacting substance of
receptors on target sites, but for this they would
anaphylaxis (SRS-A) from mast cells. Cromolyn
have to be present in sufficient local concentration
binds to a specific cromolyn-binding protein on
at the site when the antigen-antibody reaction
the mast cell surface in the presence of calcium.
occurs. This is usually not feasible since exposure
The binding protein for cromolyn on the mast
to allergens is unpredictable. The role of H1
cell surface has been suggested to be a calcium
receptor blockers is thus primarily to reverse the transporter. This transporter once occupied by
effects and reduce the symptoms after the allergic the drug is unable to transport calcium which
response has set in. Mast cell stabilizers are is essential for degranulation and release of
compounds which, as the name suggests, stabilize histamine and other mediators following antigen-
the mast cell membrane and prevent release of antibody interaction. Chromoglycate also chelates
histamine and other mediators by degranulation calcium and several other divalent cations but
following the antigen-antibody interaction. calcium chelating action is not considered to
The first mast cell stabilizing compound be responsible for preventing degranulation.
that came into clinical use was disodium Phospholipase A-induced degranulation of non-
chromoglycate (cromolyn). It was derived, like sensitized mast cells and release of chemical
many other drugs, from a plant through chemical mediators, in vitro, is inhibited by Cromolyn and
structure modifications of the parent benzopyrine this does not appear to be due to inhibition of
molecule. It was shown to provide protection enzymatic activity of phospholipase A. Another
against attacks of experimentally induced suggested mechanism thus for cromolyn induced
bronchial asthma.11 suppression of degranulation of mast cells is the
Pharmacokinetics: Disodium chromoglycate phosphorylation of a 78000 Da membrane bound
is moderately soluble in water and almost protein in the mast cells, which is integral to the
insoluble in alcohol. It is poorly absorbed by the process of histamine release. The time course of
phosphorylation by cromolyn of the membrane adverse effects with other mast cell stabilizers
bound protein and its inhibitory action on is also low primarily because of low absorption
histamine release are similar thus lending weight into circulation. Headache, however, is a common
to the possibility of such a mechanism being adverse effect observed especially with pemirolast
responsible for the observed effects. and local irritant effects may also be seen. Mast
Cromolyn does not appear to possess any cell stabilizers are contraindicated in patients
intrinsic antihistaminic, vasoconstrictor, bronch sensitive to the drug or other constituents in the
odilator, anticholinergic or anti-inflammatory ophthalmic solution.
activity. Other mast cell stabilizers, viz. nedocromil
sodium (2%), lodoxamide (0.1%) and pemirolast Dual action Agents
(0.1%), that are available for ophthalmic use are
similar in action to chromoglycate. H1 receptor blockers provide symptomatic relief
by preventing action of histamine that is released
Use of Mast Cell Stabilizers in Ocular Allergic
by degranulation of mast cells during the allergic
Disorders: The actions of mast cell stabilizer
episode. Mast cell stabilizers on the other hand are
are due to inhibition of the release of mediators
effective in preventing the release of histamine
from the sensitized mast cells when they come in
and other inflammatory mediators and hence are
contact with the antigen. Hence their therapeutic
role is mainly prophylactic whereby in the effective for preventing the attack but are of little
presence of the drug, even when sensitized mast value once the mediators have been released.
cells are challenged by antigenic exposure the Dual action agents combine receptor blocking
release of histamine and other mediators and the and mast cell stabilizing actions and are thus
subsequent allergic manifestations do not follow. useful for both symptomatic relief as well as for
Cromolyn sodium (ophthalmic solution 4%) prevention of further attacks. Agents with both
is employed as eyedrops for vernal conjunctivitis H1 receptor blocking and mast cell stabilizing
or keratoconjunctivitis. The drops are to be activities are given below in Table 13.5. Some of
administered 4 to 6 hourly.The ocular preparations them also possess additional activity against other
of mast cell stabilizers that are available for inflammatory mediators.
ophthalmic use are given in Table 13.4. Adverse effects of dual action agents: Like the
Adverse effects: Sodium chromoglycate is well mast cell stabilizers, headache, burning and
tolerated at therapeutic doses. Since topical irritation are common side-effects of dual action
administration does not result in significant drugs. Other effects include a feeling of foreign
absorption, the incidence of systemic adverse body in the conjunctiva, dry eyes and itching in
effects is low. Local effects such as irritation, and around the eyes. Systemic adverse effects are
redness and ocular and periocular itching might not marked mainly due to small amounts absorbed
be seen with topical administration but these are from the ocular site. With azelastine a bitter taste
usually mild and transient. Incidence of systemic may be felt as the drug drains into the oropharynx.
Table 13.4 Ophthalmic preparations of mast cell stabilizers

Drug Concentration in eye drops Administration
Disodium Chromoglycate (cromolyn sodium) 4% 1 to 2 drops 4–6 times daily
Nedocromil sodium 2% 1 to 2 drops twice a day
Lodoxamide tromethamine 0.1% 1 drop 4 times a day1
Pemirolast potassium 0.1% 1 to 2 drops 4 times daily
1
Two times may be sufficient in some cases
Table 13.5 Antiallergic drugs with combined H1 receptor blocking and mast cell stabilizing activities
Drug Concentration in eyedrops Comment
Azelastine 0.05% Also blocks effects of other pro-inflammatory mediators like
leukotrienes; inhibits eosinophil chemotaxis and activation
Epinastine 0.05% Also inhibits eosinophil chemotaxis; additionally blocks H2
and a receptors; rapid onset of relief after local instillation
Ketotifen 0.025% Also blocks H2 and H3 receptors; decreases chemotaxis and
eosinophil activation
Olopatadine 0.1% Also inhibits production of inflammatory cytokines
Other Drugs for Ocular Allergies allergic rhinoconjunctivitis, second generation

oral antihistamines may provide an advantage
Non-steroidal anti-inflammatory drugs have been in terms of combined effects on nasal and
considered for use in ocular allergies. However, ocular symptoms. Ketotifen, which is a mast
only ketorolac (0.5% ophthalmic solution) cell stabilizer with additional effects on release
has been found to provide beneficial effects in of inflammatory mediators, has good efficacy
seasonal allergic conjunctivitis and is approved in allergic conjunctivitis and is available as a
for such use. Ketorolac belongs to the group preparation without preservatives. This makes it
of non-selective cyclooxygenase inhibitors, the
especially suitable for use in patients who wear
pharmacology of which has been discussed in
contact lenses. Topical corticosteroids are effective
chapter 11. A 0.4 or 0.5% solution of ketorolac
but carry the risk of ocular side-effects, which
tromethamine is effective for seasonal allergic
include glaucoma, corneal ulcers and cataract.
conjunctivitis.
However, other more severe forms of ocular
Glucocorticoids are also beneficial in ocular
allergies such as vernal keratoconjunctivitis and
allergies. Besides their powerful anti-inflammatory
atopic conjunctivitis, which are chronic allergic
actions these drugs also display other mechanisms
disorders with complex pathophysiological
of action which make them useful in allergic
mechanisms, may respond better to topical
disorders. These mechanisms include inhibition
corticosteroids than to antihistamines.
of the release of histamine and other mediators
from the mast cells, basophils and neutrophils and
decreased synthesis of inflammatory mediators. OCULAR DECONGESTANTS
The detailed pharmacology of corticosteroids is
discussed in Chapter 12. Loteprednol etabonate Decongestant drugs achieve their effect primarily
(0.2%) is a steroid specifically designed for by causing vasoconstriction. Most such agents
ophthalmic allergic conditions. are sympathomimetic drugs, which act directly
A comparative evaluation of different or indirectly (by releasing noradrenaline) on a
ocular antiallergic drugs shows that topical adrenergic receptors on blood vessels to cause
antihistamines, especially those with dual vasoconstriction and consequently a decrease in
actions (e.g. olopatadine), are superior to hyperemia and a reduction in edema and mucous
mast cell stabilizers or topical NSAIDs.12 Oral secretion. Sympathomimetic drugs like ephedrine
antihistamines are not recommended as first line and pseudoephedrine act indirectly by increasing
option for allergic conjunctivitis due to their noradrenaline release while phenylephrine and
adverse systemic effects, including chances naphazoline are a receptor agonists. When
of causing dry eyes. However, for seasonal administered by systemic route their effects are
widespread and may lead to generalized increase drainage from the anterior chamber might become
in vascular tone resulting in hypertension. Other further compromised resulting in dangerous
systemic effects like excitation, sleeplessness, increase in intraocular pressure.
anxiety, nervousness and dizziness can also result. Adverse effects: Systemic effects following
Because of these limitations, topical use of these topical use are usually unremarkable in normal
agents is preferable. Ocular decongestants for individuals, because of the relatively small
topical use include phenylephrine, naphazoline, amounts entering the general circulation. However,
oxymetazoline and tetrahydrozoline. They caution is required while prescribing these drugs
are often combined with antihistaminic drugs in the presence of conditions like hypertension
for ocular use and such combinations are also or cardiovascular disorders, hyperthyroidism
available in several ophthalmic preparations. and diabetes where even mild sympathomimetic
Table 13.6 summarizes the properties of the effects might prove dangerous.
commonly used ocular decongestant preparations Local adverse effects in the eye following
and Table 13.7 shows some decongestant- topical use of decongestants are usually a
antihistamine combinations that are available in sharp irritation and a stinging sensation, which
commercial formulations. is transient. Blurring of vision might occur
Topical administration of ophthalmic solutions due to dilatation of pupil. The frequency of
of these agents into the eye produces a reduction administration should be as low as possible but
in conjunctival injection and reduces watering in any case should not exceed four times daily.
and irritation. Other effects on the eye include Tachyphylaxis can develop as also the incidence
dilatation of pupil and changes in intraocular of rebound congestion and epithelial erosion can
pressure (Table 13.6). While dilatation of pupil increase following repeated and frequent use of
may produce some blurring of vision in otherwise these agents. Decongestants are contraindicated
normal individuals, it may be especially dangerous in subjects with closed angle glaucoma due to the
in those with closed angle glaucoma in whom reasons described above.
Table 13.6 Ophthalmic decongestants

Drug1 Concentration Pupil dilatation Effect on IOP2
Phenylephrine 0.12% + +
Naphazoline 0.012–0.1% + ↑
Oxymetazoline 0.025% + -
Tetrahydrozoline 0.05% + may ↓
1
All are formulated as hydrochloride salts for ophthalmic solution.
2
IOP: Intraocular pressure
Table 13.7 Decongestant-antihistamine combinations

Decongestant Antihistaminic
Pyrilamine Pheniramine Antazoline
Phenylephrine
0.12% 0.1% - -
0.125% - 0.5% -
Naphazoline
0.025% - 0.3% -
0.05% - - 0.5%
FUTURE DIRECTIONS that these may be playing a significant role in

conditions like allergic conjunctivitis.16 Some H4
In the past, development of drugs for relief of receptor antagonists are currently in the stage of
episodic allergies has remained focused mainly early clinical trials.17-19 These and other similar
on histamine and mast cells as the targets. Over agents may be added in future to the drugs that
the last two decades several other aspects have are available for the treatment of ocular allergies.
attracted the attention of researchers. Thus,
although histamine is the primary chemical
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co-localized with H1 receptors with a higher hydrochloride ophthalmic solution 0.1%)
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in acute allergic conjunctivitis in the conjunctival 15. Kalpaxis JG, Thayer TO. Double-blind trial of
allergen challenge model. Acta. Ophthalmol pentigetide ophthalmic solution, 0.5%, compared
Scand. 2000;78(230):60–3. with cromolyn sodium, 4%, ophthalmic solution
10. Leon J, Charap A, Duzman E, Shen C. Efficacy of for allergic conjunctivitis. Ann Allergy. 1991;
cimetidine/pyrilamine eyedrops, a dose response 66(5):393–98.
study with histamine challenge. Ophthalmology. 16. Abelson MB, McLaughlin J. Ocular antihis
1986;93(1):120–3. tamines revisited: Beyond H1. Rev Ophthalmol.
11. Altounyan REC. Inhibition of experimental asthma 2011;18(4):66–70.
by a new compound, disodium cromoglycate, 17. Torkildsen G, Shedden A. The safety and efficacy
‘INTAL’. Acta Allergol. 1967;22:487. of alcaftadine 0.25% ophthalmic solution for the
prevention of itching associated with allergic con-
12. del Cuvillo A, Sastre J, Montoro J, Jauregui I, Davila
junctivitis. Curr Med Res Opin. 2011;27(3):623–31.
I, Ferrer M, et al. Allergic conjunctivitis and H1
18. Engelhardt H, Smits RA, Leurs R, Haaksma E,
antihistamines. J Investig Allergol Clin Immunol.
de Esch IJ. A new generation of anti-histamines:
2009;19(1):11–8.
Histamine H4 receptor antagonists on their way
13. Geha RS, Helm B, Gould H. Inhibition of the to the clinic. Curr Opin Drug Discov Devel.
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E-chain fragment synthesized in E. coli. Nature. 19. Strakhova MI, Cuff CA, Manelli AM, et al. In
1985;315(6020):577–8 vitro and in vivo characterization of A-940894:
14. Hamburger RN. Peptide inhibition of the A potent histamine H4 receptor antagonist with
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(4200):389–90. 2009;157(1):44–54.
ChapteR 14
Local Anesthetics in
Ophthalmology Practice
OVERVIEW local anesthesia in an expert hand carries a very

low risk of serious complications.2 Even though,
Anesthesia for ophthalmic surgery has undergone in one of the studies, patients reported seeing light
tremendous changes over the past few decades. flashes during the surgery that were considered
The earliest authentic description on this subject terrifying experience for significant number of
was probably provided by the ancient Indian them,2 regional or topical anesthesia is still the
surgeon Sus’ruta in 600 BC. Since those days, most popular type of anesthesia for ophthalmic
ophthalmic surgery has reshaped by evolution of surgery.3 The relevant anatomical considerations
anesthesia, both in terms of the introduction of new for the techniques of administration of local
local anesthetic agents as well as development of anesthesia are described in Chapter 1.
new techniques of administration.
Currently, there are two major approaches for
ophthalmic anesthesia—general anesthesia and PHARMACOLOGY OF LOCAL
local anesthesia. The decision to choose between ANESTHETIC AGENTS
these two approaches involves the surgeon in
terms of suitability for the type of surgery; the Local anesthetic agents are used to produce
anesthesiologist in terms of appropriateness transient loss of sensation and motor paralysis in a
of the patient’s general physical condition to specific area or part of the body. These agents are
that specific anesthetic approach and lastly and capable of producing reversible block of action
equally important, is the patient’s acceptability.1 potential propagation, which is responsible for
Nowadays, majority of the ophthalmic surgeries nerve conduction in any part of nervous system
can be performed under local anesthesia, while, and in all types of nerves including sensory and
general anesthesia is kept as an alternative option motor nerves.
for special situations like uncooperative patients Cocaine was the first local anesthetic agent
(e.g. children), bilateral surgery, and extensive isolated by Niemann in 1860 and was used at first
or lengthy procedures. This preference for local for ophthalmic anesthesia. Although, it was soon
anesthesia despite insignificant difference in discovered that cocaine is highly addicting, it
morbidity and mortality profiles is due to several remained in use for about 30 years until procaine
advantages that local anesthesia offers over was synthesized by Einhorn in 1905.4 An ideal
general anesthesia such as less post-operative risk local anesthetic is expected to provide rapid
of nausea and vomiting, superior post-operative onset and long duration of action without local
pain control, shorter post-operative recovery and systemic toxicity. None of the currently
time and ability of the patient to maintain mental available agent possesses all desirable properties
alertness during surgical procedure. Furthermore, and synthesis of newer agents continues.
Local Anesthetics in Ophthalmology Practice 195
Local anesthetic agents consist of a lipophilic gel, while all injectable local anesthetics are of
group linked to an ionizable group by an amide type (except procaine). The reason behind
intermediate chain. This intermediate chain is replacement of injectable esters by amides apart
either an ester or an amide link (Fig. 14.1). from cocaine’s addiction risk is that they are
Besides the chemistry and general physical metabolized to para-aminobenzoic acid (PABA)
properties, specific stereochemical configurations which is known for its potential to cause allergy.4
of local anesthetic agents also determine their For topical use, the case is different as there is
potency. Based on their chemical structure, local less systemic absorption and much lower risk of
anesthetic agents are divided into two classes: allergic reaction due to PABA. At the same time,
1. Amino esters: Possess an ester linkage amino-esters provide rapid onset of action, which
between the benzene ring and the amine side lasts for brief duration.
chain. Topical and injectable anesthetics used in
2. Amino amides: Possess an amide linkage ophthalmic practice are listed in Table 14.1 and
between the benzene ring and the amine side 14.2.
chain.
At present, all commonly used topical Pharmacokinetics
anesthetics are of the ester type except lidocaine
Local anesthetics are injected or instilled
locally close to nerve fibers that need to be
blocked. Uniquely, local anesthetics reach their
site of action before they reach the vascular
compartment, in contrast to other drugs that
are distributed from the vascular compartment
to their sites of action. In other words, the
appearance of local anesthetic in the vascular
compartment represents the termination of their
action. Therefore, the duration of their action is
affected by the rate at which they are removed
from their local site of injection or instillation
into the systemic circulation. The extent of
Figure 14.1 Chemical structure of local anesthetics their systemic absorption also determines the
likelihood of their systemic adverse effects.6
Table 14.1 Topical anesthetics
Preparation Class Formulation Onset Duration Commonly used

preservative
Tetracaine Ester 0.5% solution 1 minute 15–20 Chlorobutanol (0.4%)
hydrochloride minutes
Proparacaine Ester 0.5% solution 6–20 seconds 10–15 Benzalkonium chloride
hydrochloride minutes (0.01%), Chlorobutanol (0.2%)
Proparacaine Ester 0.5% solution with 6–20 seconds 10–15 Thimerosal (0.01%)
hydrochloride 0.25% sodium minutes
with fluorescein fluorescein
Benoxinate Ester 0.4% solution with 1–2 minutes 10–15 Chlorobutanol (1.0%)
hydrochloride 0.25% sodium minutes
with fluorescein fluorescein
Lidocaine gel Amide 1.5, 2, 3.5 and 4% 1–5 minutes 15–40 Preservative free
gel minutes
Table 14.2 Injectable anesthetics
Preparation Class Formulation (% solution) Onset (min) Duration (min)
Procaine Ester 1, 2, 10 7–8 30–45

Lipocaine Amide 0.5, 1, 1.5, 2, 4 4–6 40–60
Mepivacaine Amide 1, 1.5, 2 3–5 120–180
Bupivacaine Amide 0.25, 0.5, 0.75 5–10 240–720
Etidocaine Amide 1, 1.5 3–5 180–600
Prilocaine Amide 4% 2–3 150–108
Local Absorption and Distribution injected in infected and inflamed tissue, local
anesthetics have poor efficacy as they exist largely
The availability of a local anesthetic agent to in ionized form due to highly acidic local pH and
nerves depends upon its ability to diffuse through penetrate the lipid membranes poorly.9,10
the tissue and the outer lipid membrane of nerve It has been reported that topical application of
fibers to reach its site of action. The movement local anesthetics increases corneal permeability of
through the nerve fiber membranes depends upon subsequently applied drugs and mydriatics, like
the lipid solubility of the local anesthetic agent. phenylephrine, if applied after the application
The small and highly lipid soluble molecules of local anesthetic agents, produce faster
interact faster with the sodium channel receptors. mydriasis. The pupillary dilatation is larger and
While lipid solubility helps in penetration through lasts longer.10-12 Similarly, prior application of
the neuronal membrane, water solubility helps the proparacaine also increases the mydriatic and
local anesthetic to be in the cationic form, which cycloplegic effect of tropicamide.13 However,
binds to anionic fragments of the specific receptor this finding was questioned by a recent study,
sites in voltage gated sodium channels.7 which could not find any significant effect of
Therefore, the potency of local anesthetic topical local anesthetic application on ocular drug
agents is positively correlated with their lipid delivery.14 Moreover, local anesthetics reduce the
solubility, as long as the water solubility is tear flow15 and thus might enhance the amount of
retained. drug absorption through cornea by reducing the
The pH of the tissue in which the drug is washout effect of tear flow.16 Increased corneal
injected also affects its diffusion. Local anesthetic absorption reduces the amount of systemic
agents are weak bases but for clinical use they are absorption, thus reducing the systemic toxicity.
available as salts to increase their solubility and
stability. The pKa of the local anesthetic solutions
ranges from 8.00 – 9.00. Therefore, when injected Systemic Absorption and Distribution
in the body, at physiological pH their larger Systemic absorption of local anesthetics is the
fraction exists as charged cationic form8,9 as is means for their local elimination and termination of
shown by Henderson-Hesselbalch’s equation: action. The extent and rate of systemic absorption
of local anesthetics is determined by the dose,
Log (cationic form/unionized form) = pKa – pH
site of injection, extent of tissue protein binding,
The unionized form, being highly lipid soluble physicochemical properties and presence of
helps in the penetration of drug through the outer vasoconstrictor substance. Injection of a local
lipid membranes of nerve fibers whereas ionized anesthetic agent in a highly vascular area (e.g.
form is most active at the receptor site as it cannot muscles) will lead to higher amount of systemic
easily leave the closed channels. Therefore, when absorption as compared to that after its injection
in a poorly vascularized area (e.g. subcutaneous of vision. Nevertheless, a balance should be always
tissue). The duration of action of local anesthetics sought between the cardiac risk and the benefits of
is proportional to the time for which they remain epinephrine with regards to the quality and duration
in contact with nerve or local tissue. All local of anesthesia and level of pain control.19
anesthetic agents have intrinsic vasodilating activity The enzyme hyaluronidase is often added
except cocaine, which has vasoconstrictor activity. to local anesthetic solution for retrobulbar
Thus, local anesthetic agents promote their own and peribulbar injections to facilitate its local
removal from the site of injection, which affects distribution. Hyaluronidase depolymerizes
their duration of action. For example, lidocaine the hyaluronic acid, which is a component of
has shorter duration of action as compared to connective tissue and acts as tissue cement. The
mepivaciane due to its enhanced vasodilating breakdown of hyaluronic acid allows easy spread
property.17 Drugs like bupivacaine and etidocaine of the solution in the tissue.18 A usual dose of 75
have high protein binding, which reduces the units (0.5 mL) per 10 ml of anesthetic solution
amount of free drug available to interact with the produces enhanced akinesia and anesthesia.20
receptor. But this high protein binding acts as a drug Once into the systemic circulation, amide local
reservoir and prolongs the duration of action of anesthetics are widely distributed. At first into the
these drugs.7 Addition of a vasoconstrictor such as highly vascular tissues like CNS, liver, kidney
epinephrine causes local vasoconstriction, thereby and brain, followed by less vascular tissues like
reducing the rate and extent of systemic absorption. gastrointestinal tract and muscles. Ester type of
This causes increased local availability of the local agents have a very short half-life as they undergo
anesthetic and enhanced neuronal uptake. Co- rapid metabolism before they are distributed to
administration of epinephrine, therefore, improves various tissues.
the onset, provides better quality and increases
duration of anesthesia. Epinephrine also reduces Metabolism and Excretion
local bleeding and the risk of systemic toxicity
Metabolism of local anesthetics in plasma
to local anesthetic agent by reducing its systemic
or liver converts them into highly water
absorption. Epinephrine can delay the wound
soluble forms for easy excretion in urine. Ester
healing and can occasionally cause tissue necrosis
type of local anesthetics such as procaine is
due to intense vasoconstriction.7 Epinephrine quickly metabolized by pseudocholinesterase
can also cause anxiety, restlessness, tremors, (butyrylcholinesterase) and, therefore, has a
palpitations, pallor, hypertension, headache and short half-life. Amide types are metabolized by
precordial discomfort. The usual concentration of hepatic microsomal cytochrome P450. Individual
epinephrine used in ophthalmic preparations ranges amide agents are metabolized at different rates by
from 1:50,000 to 1:200,000. The effect of adding microsomal enzymes. Concomitant use of other
epinephrine is especially prominent with short- and drugs that inhibit the same cytochrome enzyme
medium acting local anesthetics. Relatively less may potentiate the action of amide type of local
efficacy of epinephrine to prolong action of long- anesthetic agents. Toxicity of amide types is
acting agents is due to their high lipid solubility also more likely in patients with impaired liver
and high tissue protein binding.18 Addition of a functions or reduced hepatic blood flow due to
vasoconstrictor has no effect on the duration of their reduced hepatic metabolism.7
topical anesthesia but increases the risk of systemic
adverse effects, and therefore, is not recommended. Mechanism of Action
Use of epinephrine is relatively contraindicated
in patients with hypertension and ischemic heart Local anesthetics act by blocking the voltage-
disease. In patients with glaucoma, epinephrine can gated sodium channels in nerve fibers. The
cause severe local vasospasm and permanent loss action of sodium pump is crucial in maintaining
the transmembrane ionic gradients required for while resting stage is relatively resistant to the
impulse conduction in excitable membranes such blocking effect of local anesthetics. Rapidly firing
as neuronal fibers and cardiac muscles. During nerves are more susceptible to the action of local
excitation the resting membrane potential of –90 anesthetic agents as their membrane voltage is
to –60 mV changes to +40 mV due to rapid influx more positive than normal, which facilitates the
of sodium ions through the open sodium channels. interaction of local anesthetic molecule with the
During this membrane depolarization, sodium receptor.9 Additionally, rapidly firing neurons pass
channels pass into an active stage and potassium through the open and inactive stages of sodium
channels open. Outward flow of potassium channels more often than the resting fibers and,
ions causes membrane repolarization, return therefore, are more sensitive to the action of local
of membrane potential to –95 mV and return anesthetics. Recovery of sodium channels from
of sodium channels to resting stage. Sodium inactive to resting stage after being blocked by
channels in resting stage can again pass into active local anesthetics is much slower as compared to
stage at the arrival of new impulse. that from normal inactivation. Local anesthetics,
During the entire process of membrane therefore, increase the refractory period and reduce
depolarization and repolarization, the sodium the frequency of nerve conduction (Fig. 14.2).
channels pass through three conformational As mentioned before, sodium channels in
changes or stages, the resting stage in which the resting stage are less sensitive to local anesthetic
entry of sodium is blocked at its activation gate action as compared to open and inactive channels
near extracellular site, activated stage in which and thus, increased extracellular calcium
both the inactivation and activation gates are open concentration partially antagonizes the action
to allow rapid entry of sodium ions and finally of local anesthetics by favoring the resting
inactive stage when the inactivation gates near stage, whereas increased extracellular potassium
intracellular site are closed and sodium entry is enhances the effect of local anesthetics by
blocked. The inactive channels are in a refractory favoring the inactive stage of sodium channels.7
stage and must return to resting stage before they The susceptibility of nerve fibers to blockade
become available for activation once again. The of impulse conduction by local anesthetics is also
return of inactive channels to resting stage is time influenced by: size of the nerve fibers, myelination
dependent.8 and position of nerve fiber in the nerve bundle.
Local anesthetics bind to the receptors near The fibers with smaller diameter are blocked
the intracellular end of sodium channel and faster than those with larger diameter. Myelinated
block them in the inactive and active stages, nerves are blocked faster than the unmyelinated
Figure 14.2 Representation of voltage-gated sodium channels showing the site and
mechanism of action of local anesthetics
nerves of the same diameter. In large peripheral drying. Clinically, the changes manifest as
nerves, motor fibers are located peripherally and eyelid edema, conjunctival hyperemia, papillary
are, therefore, exposed first to locally administered hypertrophy, mucopurulent discharge, corneal
anesthetic agent. As a consequence, motor nerve epithelial defects which can progress to stromal
block may appear faster than the sensory block. In infiltration, keratic precipitates, anterior uveitis,
the extremities, sensory fibers for proximal parts hypopyon and hyphema. Appearance of a dense
are located outside the sensory fibers for distal yellowish white stromal ring is characteristic of
parts. Therefore, sensory loss appears first for corneal damage due to anesthetic misuse and
proximal areas followed by distal areas.10 abuse.23
The local anesthetics act on all excitable
membranes, such as CNS neurons and cardiac Systemic
cells, in the same way as on peripheral neuronal
membranes. Therefore, at very low concentration Systemic toxicity to topically applied anesthetics
they can be useful as antiarrhythmic agents but at is relatively uncommon and is usually seen with
high concentration are likely to cause arrhythmias drug overdose. Drug overdose can cause high
and CNS adverse effects. blood levels leading to toxicity.
Injectable local anesthetics can cause systemic
adverse effects after extravascular administration.
Adverse Effects Inadvertent intravenous injection can cause
Local serious toxicity. The degree of systemic toxicity
correlates with the potency of the anesthetic
Topically applied local anesthetics, like tetracaine, agent. Accordingly, bupivacaine and tetracaine
cause mild local stinging and burning sensation. are more likely to cause toxicity as compared to
Such symptoms are short lasting and do not prilocaine and lidocaine. Among the agents with
require specific treatment. In some patients similar potency, the likelihood to cause toxicity
corneal epithelial damage occurs due to tear varies according to the extent of absorption and
film instability caused by decreased reflex
metabolism. For example: after subcutaneous
tearing, increased tear evaporation and infrequent
administration, prilocaine is less readily absorbed
blinking. 21 Superficial punctate keratopathy
and is more readily metabolized as compared to
is infrequent and usually mild. Local allergic
lidocaine and, therefore, toxicity of prilocaine
reactions are uncommon. They may present as
is 60 percent lower than that of lidocaine. The
conjunctival hyperemia, chemosis, swelling of
systemic adverse effects of local anesthetic agents
eyelids, lacrimation and itching. The allergic
mainly involve CNS and cardiovascular system.9
reactions are more likely with ester types as
The central nervous system excitation repre
compared to amides.
sents the earliest sign of toxicity. Initial symptoms
Repeated long-term administration of topical
anesthetics causes delayed wound healing and consist of a feeling of light headedness, dizziness
is associated with infiltrative keratitis. Local followed by visual disturbances, tinnitus,
anesthetics may be used to relieve initial ocular drowsiness, disorientation, slurred speech, muscle
pain and should not be prescribed for self- twitching and temporary loss of consciousness.
administration as virtually all local anesthetics Tremors of face and extremities may be followed
can cause corneal damage on prolonged use.22 by convulsions. The CNS excitation may be
Frequent instillation of local anesthetics even for followed by respiratory arrest and generalized
a few days causes increased corneal permeability CNS depression.7
and loss of corneal epithelium and tear film Cardiovascular adverse effects of local anesthetics
instability. Reduced corneal sensations cause are attributed to their direct action on heart,
reduced blinking, which further enhances corneal peripheral actions on blood vessels and blockade
of conduction in autonomic fibers. Myocardial injury, topical application of anesthetic agents
suppression and vasodilation due to direct can cause endothelial damage.
relaxant effect on blood vessels causes decrease
in cardiac output. All local anesthetic agents show
similar cardiovascular toxicity.7 TYPES OF LOCAL ANESTHESIA
Methemoglobinemia leading to cyanosis is an Types of local anesthesia that are used for
adverse effect of the high doses of prilocaine. ophthalmic procedures include:
Prilocaine metabolizes to orthotoluidine, which 1. Retrobulbar block
upon accumulation, oxidizes hemoglobin to 2. Peribulbar block
methemoglobin. Reducing agents like methylene 3. Sub-Tenon’s block
blue or ascorbic acid are used to reduce 4. Local infiltration
methemoglobin to hemoglobin.7 5. Topical
Allergic reactions to amino-esters are seen in
small percentage of population. Esters metabolize Retrobulbar Block
to PABA, which is responsible for allergic
reactions such as dermatitis and rashes. Amino- Retrobulbar block is a suitable anesthetic
amides do not metabolize to PABA and, therefore, technique for majority of ophthalmic surgical
allergic reactions with amides are rare.7 procedures (such as cataract extraction, glaucoma
filtering procedures, iris surgery, trans-pars-plana
Contraindications vitrectomy, or orbital exploration) with or without
addition of a second injection in the superior nasal
Patients with previous history of hypersensitivity quadrant.25
should not be given the same anesthetic agent. It is performed by injecting the local anesthetic
However, an agent from different chemical solution inside the muscle cone behind the globe
group may be tried. Amide type of local (Fig 14.3). The injection is made just above the
anesthetic agents are metabolized in liver inferior orbital margin in the inferotemporal
and, therefore, should be used with caution quadrant. The needle is inserted parallel to
in patients with impaired liver function. Ester the orbital floor and then is directed upwards
type of local anesthetics are metabolized by and medially and local anesthetic is injected
plasma pseudocholinesterase and, therefore, after ruling out intravascular location of the
are contraindicated in patients with genetic needle. Retrobulbar block provides global and
deficiency of the enzyme. Topically applied conjunctival anesthesia due to the conduction
anesthetics cause tear film instability and reduced block in the intraorbital sensory division of
reflex tearing and thus can complicate the the ophthalmic branch of trigeminal nerve. For
clinical picture in dry eye patients. In such cases global akinesia, conduction block of oculomotor,
anesthetic agents should be used after complete trochlear and abducent nerve is required. Since
evaluation for dry eye condition.23 In conditions the injection is made inside the cone and trochlear
requiring collection of specimen from ocular nerve runs an extraconal course, activity of
surface for culture, instillation of anesthetic superior oblique muscle is retained.
agent should be done after specimen collection as This block requires merely, 2 to 4 mL, of
many of these agents have antimicrobial activity, local anesthetic to produce adequate retrobulbar
though, it is suggested that proxymetacaine anesthesia. Almost any of the local anesthetic
0.5% can be used as it has minimal antibacterial agents can be used but many ophthalmologists
effects in vitro.24 In patients with perforating favor a combination of bupivacaine and lidocaine.26
Conversely, for peribulbar approach, needle including skin, orbicularis muscle, orbital
does not advance into the muscle cone and, septum and anterior tarsal surface, a pretarsal
therefore, slightly larger volume, 4-6 ml is block is given. For surgery involving palpebral
needed. conjunctiva and posterior tarsal surface, a
retrotarsal block is given. The procedure requires
Peribulbar Block subcutaneous administration of 0.5 to 1.0 mL of
solution along the proximal tarsal border. A gentle
Peribulbar block is achieved by injecting local massage over the injected area facilitates spread
anesthetic outside the muscle cone (Fig 14.3). of solution and reduces the chance of hematoma
This helps to avoid proximity of the needle to formation.27,28
optic nerve. The method requires larger quantities
of local anesthetic solution. The injection is made
Topical
just above the lateral one third of inferior orbital
rim. If a second injection is required it is made Topical application is the most commonly
in more medial position to achieve complete used method of administering local anesthesia.
akinesia.27 A pressure lowering device is used to Majority of topically applied local anesthetic
spread the anesthetic agent and soften the eye. agents provide similar onset, depth and duration of
anesthesia. Topical anesthesia is used for common
Sub-Tenon’s Block diagnostic procedures such as applanation
tonometry and gonioscopy. Procedures like
Sub-Tenon’s block requires administration of removal of small superficial foreign body,
anesthetic agent under the Tenon’s fascia. Tenon’s suture removal can be done under topical
fascia is incised 5–10 mm lateral to limbus. A anesthesia. Intraocular procedures such as
cannula is inserted under the Tenon’s fascia for phacoemulsification are now done under topical
injection of local anesthetic agent.27,28 anesthesia. Some specialized procedure like
forced duction test, electroretinography, corneal
Local Infiltration epithelial debridement are also performed under
Injection of local anesthetic agent by local topical anesthesia.
27,28
infiltration is commonly used for eyelid surgery.

To achieve anesthetic effect in anterior lamella FUTURE OF LOCAL ANESTHETICS IN
OPHTHALMIC SURGERY
Future advances in local anesthetic use in
ophthalmic surgery might involve the topical
application of a new local anesthetic like
neosaxitoxin, which is a phycotoxin. It has the
capability of reversibly blocking neuronal voltage-
gated sodium channels.29 It has been shown in a
recent study that neosaxitoxin has a promising
long acting profile of local anesthetic effect when
compared to bupivacaine for post-operative pain
control.30 Furthermore, future prospects might
not be limited to merely prolongation of local
anesthetic effect, but could extend to the control
Figure 14.3 Schematic diagram showing sites of
of the duration of action of the local anesthetics.
injection for retrobulbar and peribulbar block For example use of a reversibly acting vasodilator
phentolamine mesylate,has been shown to 11. Jauregui MJ, Polse KA. Mydriatic effect using
have a safe profile and a promising success in phenylephrine and proparacaine. Am J Optom
decreasing the duration of local anesthesia in Physiol Opt. 1974;51(8):545–9.
dental practice.31,32 In a recent clinical study, it 12. Kubo DJ, Wing TW, Polse KA, Jauregui MJ.
Mydriatic effect using low concentration of
was found that phentolamine mesylate has a
phenylephrine hydrochloride. J Am Optom
high rate of acceptance from both the patients Assoc. 1975;46(8):817–22.
and the dentists.33 Its utility in ophthalmic practice 13. Mordi JA, Lyle WM, Mousa GY. Does prior
remains to be determined. instillation of topical anesthetic enhances the
effect of tropicamide? Am J Optom Physiol Opt.
1986;63(4):290–3.
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Am J Optom Physiol Opt. 1977;54(5):276–81. Retrobulbar block. In: Peripheral Nerve Blocks:
A Color Atlas, 3rd edn. Lippincott Williams & of Neosaxitoxin versus bupivacaine via port
Wilkins. 2008; pp.173–7. infiltration for postoperative analgesia following
26. Brown DL. Head and Neck Blocks: Retrobulbar laparoscopic cholecystectomy: A randomized,
(Peribulbar) Block. In: Atlas of Regional. double-blind trial. Reg Anesth & Pain Med. 2011;
Anesthesia, 4th edition. Saunders, Elsevier. 2010; 36(2):103-9.
pp.171-76. 31. Tavares M, Goodson JM, Studen-Pavlovich D,
27. Hadzic A. Chapter 18 Local & Regional Yagiela JA, Navalta LA, Rogy S, et al. Soft
Anesthesia for Eye Surgery. In: Textbook of Tissue anesthesia reversal group. Reversal of
Regional Anesthesia and Acute Pain Management, soft-tissue local anesthesia with phentolamine
1st edn. The McGraw-Hill Companies. 2007. mesylate in pediatric patients. J Am Dent Assoc.
28. Basta SJ. Chapter 65 Anesthesia for Ophthalmic 2008;139(8):1095–104.
Surgery. In: Longnecker et al. Anesthesiology. 32. Laviola M, McGavin SK, Freer GA, Plancich
The McGraw-Hill Companies. 2008; pp. 1565- G, Woodbury SC, Marinkovich S, et al. Rando
71. mized Study of phentolamine mesylate for
29. Rodríguez-Navarro AJ, Lagos N, Lagos M, reversal of local anesthesia. J Dent Res. 2008;
Braghetto I, Csendes A, Hamilton J, et al. 87(7):635–9.
Neosaxitoxin as a Local Anesthetic: Preliminary 33. Saunders TR, Psaltis G, Weston JF, Yanase RR,
Observations from a First Human Trial. Anesth Rogy SS, Ghalie RG. In-Practice Evaluation
esiology. 2007;106(2):339–45. of oraverse® for the reversal of soft-tissue
30. Rodríguez-Navarro AJ, Berde CB, Wiedmaier G, anesthesia after dental procedures. Compend
Mercado A, Garcia C, Iglesias V, et al. Comparison Contin Educ Dent. 2011;32(5):58–62.
ChapteR 15
Immunomodulators
OVERVIEW to manage Type IV hypersensitivity reactions,

immunosuppressive therapy is routinely adopted;
Classically, immunity is defined as the defense the mainstay of which is the drug, cyclosporine
mechanism of body that is responsible for (CsA). In addition, drugs such as azathioprine,
prevention of entry and elimination of pathogens steroids, rapamycin and mycophenolate
and other exogenous agents (dust, pollens, foods, mofetil are also used to widen the umbrella of
drugs, microbiologic agents, chemicals, and many immunomodulation.
blood products). In the absence of systematic
immune response, contact with antigen can
lead to acute or chronic inflammation and tissue OCULAR ALLERGIES
damage. In the condition of blood transfusion
reactions and organ/tissue graft rejection, immune Industrialized countries are witnessing a spate
reactions have been established to be evoked by of allergic conditions as about 30% of people
endogenous homologous tissue antigens. Another are reported to have one or the other form of
category of immune reactions is initiated by self allergic disease and more importantly, 40–80%
or autologous antigens, and is categorized as of these have allergic symptoms in the eyes.1
autoimmune diseases. Ocular inflammation is usually a localized allergic
Hypersensitivity reactions are immune condition that manifests as red and itchy eyes,
responses caused by humoral or cell-mediated lacrimation that may sometimes be associated
immune mechanisms in response to exogenous with rhinitis. Clinically, conjunctivitis, blepharitis,
antigen and usually vary from itching of blepharoconjunctivitis, or keratoconjunctivitis are
skin, to bronchial asthma. On the basis of the identified as conditions of ocular inflammation.
immunologic mechanism that mediates the In the cascade of events leading to ocular
disease, hypersensitivity reactions can be further inflammation, two phases have been identified-
classified as—Type I or immediate, Type II or early and late. In the early phase, the mast cells
antibody-mediated, Type III or immune complex- are activated, and in late phase the inflammatory
mediated and Type IV or cell-mediated. cells are recruited to the site of inflammation. As
The cell-mediated hypersensitivity is initiated part of the first response to allergen insult, the
by antigen-activated T lymphocytes (CD 4+ and mast cells degranulate to release histamine from
CD8 + T cells) and may manifest as delayed intracellular storage sites and at the same time
type hypersensitivity reaction or direct cell initiate the de novo synthesis of other mediators
cytotoxicity. This type of hypersensitivity reac like leukotrienes and prostaglandins. These
tion is commonly seen in rheumatoid arthritis, events can be observed within first fifteen minutes
transplant rejection, tumor immunity, etc. In order of the antigen attack. Mast cell degranulation
Immunomodulators 205
also activates vascular endothelial cells and 2. Alkylating agents: Cyclophosphamide and
fibroblasts that help to amplify inflammation. chlorambucil
Further, in response to the chemotactic factors 3. Antimetabolites: Methotrexate, mycophenolate
that are released by mast cells, an accumulation mofetil and azathioprine
of eosinophils and neutrophils at the site of 4. Viral replication Inhibitors: Human Re
inflammation can be observed. combinant Interferon (INFa2a, INFa2b)
Lymphocytes (T and B cells) are also important These immunomodulating agents provide
mediators of allergic reactions and are divided alternative to corticosteroid-based immuno
into CD4+ helper T cells (Th) and CD8+ killer T suppressive therapy. Currently, these agents
cells (Tk). The antigen-presenting cells (APCs) are also indicated as first-line therapy for the
in the conjunctiva present the antigen to CD4+ treatment of systemic inflammatory diseases with
T cells, which then initiate the inflammatory destructive ocular sequela, e.g. Behçet's disease
reaction. and granulomatosis with polyangiitis (Wegener's).
In most cases of ocular inflammation, normal However, use of systemic immunosuppressive
visual acuity is maintained. But some severe agents has to be carefully monitored in order
forms of ocular inflammation such as allergic to derive maximum therapeutic benefit, and
conjunctivitis and vernal keratoconjunctivitis minimize the potential side-effects, to afford
(VKC), may culminate in visual impairment, due favorable long-term outcome. In fact, it is now
to corneal damage or corneal curvature change. advocated that in cases of therapy-resistant,
Therefore, the main goal in the management severe ocular allergies (like conjunctivitis or
of allergic eye diseases is to reduce inflammation rhinoconjunctivitis), the immunotherapy should
followed by prevention of the associated be initiated early so that the quality of life and
complications such as vision impairment, dry patient compliance is improved.
eye, etc.
Current Immunomodulatory Option CYCLOSPORINE

for Ocular Allergies CsA, a cyclic polypeptide of 11 amino acids,
is produced by the fungus Beauveria nivea.
Current drug treatment for ocular allergy focuses
CsA ophthalmic emulsion (Restasis ®, 0.05%)
on control of inflammation. Conventionally,
is the only formulation currently approved by
besides antihistaminics, corticosteroids have
the Food and Drug Administration as topical
been used as the mainstay in the management of
immunomodulator with anti-inflammatory effects
ocular allergies. Severe morbidities associated
for the treatment of dysfunctional tear syndrome
with the use of corticosteroids and their failure
and in patients whose tear production is presumed
to treat the cause of allergy and prevent its
to be suppressed due to ocular inflammation,
recurrence, has become the major limitation
associated with keratoconjunctivitis sicca.
and this has lead to development of alternative
Another topical ophthalmic preparation of CsA
management modalities. Detailed pharmacology (0.1%) is under investigation in Phase II trials for
of corticosteroids, antihistaminics and mast cell immunomodulator and immunosuppressive action.
stabilizers is discussed in Chapters 12 and 13.
The complete bouquet of immunomodulating
drugs available for treatment of ocular allergy are
Mechanism of Action
subdivided into the following categories based on CsA has been shown to be effective in suppression
their specific mechanism of action: of T-cell dependent immune reactions and humoral
1. Calcineurin inhibitors: CsA, tacrolimus and immunity-mediated ocular allergic inflammation.
sirolimus It mainly acts by suppression of Th2-lymphocyte
proliferation, interleukin (IL)-2 and IL-5 production Cyclosporine Formulations
and chemotaxis of eosinophils.
At the outset of inflammatory reaction, when CsA is a lipophilic drug and ensuring its
antigen binds to the receptor located on T-cell absorption into ocular tissues following topical
membrane it leads to increase in intracellular administration is a challenge. Consequently, CsA
calcium levels (Fig. 15.1). Intracellular calcium is formulated for clinical administration using
stimulates dephosphorylation of Nuclear Factor castor oil. In order to increase the therapeutic
of Activated T-cells (NFAT), and simultaneously efficacy of CsA and decrease its adverse effects,
translocates to nucleus. Consequently, transcription various drug development approaches such as
of immunoproliferating genes is activated with preparation of solid formulations, liposomes,
release of cytokines such as IL-2, IL-5. micelles, emulsions and microemulsions,
On the other hand, CsA exerts immuno microspheres, nanoparticles, and physical
suppressive action by selective inhibition of IL-2 or chemical enhancers have been adopted.
release during T-cell activation. CsA forms a Another strategy to enhance the penetration
complex with cyclophilin, a cytoplasmic-receptor of the lipophilic CsA through ocular tissues
protein present in target cells (Fig. 15.1). CsA is the synthesis of a chemically modified pro-
-cyclophilin complex further binds to calcineurin drug, which is hydrophilic. This form of CsA is
and this complex inhibits Ca 2+ stimulated inactive and is transformed into the active form
dephosphorylation of the cytosolic component within the tissues and provides efficient delivery
of NFAT. As translocation of cytoplasmic of the drug.
dephosphorylated NFAT to the nucleus is required Other developments regarding delivery of
for activation of immunoproliferating gene CsA to ocular tissue include preparation of
transcription, the cascade is truncated at this stage punctal plug that is composed of Hydroxyl Ethyl
leading to failure of T-cell activation in response Methacrylate (HEMA) and Ethylene Glycol
to specific antigenic stimulation. Dimethacrylate (EGDMA).2
Figure 15.1 CsA—cyclophilin A complex binds to calcineurin to inhibit intracellular

signaling process involved in inflammation
Therapeutic uses Adverse Effects and Drug

Dry Eye Syndrome Interactions
The principal adverse reactions to CsA therapy
Healthy tears are essential for protecting and
are renal dysfunction, hypertension, tremor,
nourishing the ocular surface and serve as a
hirsutism, hyperlipidemia and gum hyperplasia.
protective sheath. However, the condition of
Sirolimus aggravates CsA-induced renal
dysfunctional tears clinically manifest as Dry
dysfunction, while CsA increases Sirolimus-
Eye Syndrome (DES) that has become a growing
induced hyperlipidemia and myelosuppression.
problem in urban cities owing to various factors
This has led to the recommendation that the
such as pollution, stress, etc. Central to the etiology
administration of the two drugs should not be
of DES lies ocular surface inflammation and
done at the same time.
conventional management includes application
of topical anti-inflammatory drugs, on one hand
and promoting the secretion of healthy tears on the Tacrolimus
other. Wide variety of artificial tear formulations Two calcineurin phosphate inhibitors namely,
containing electrolytes and solutes and having Tacrolimus (Protopic ® , 0.03% and 0.1%
compatible osmolarity, viscosity, preservatives ointments) and Pimecrolimus (1% cream) are also
etc., are available. The pharmacology of these available for ophthalmic use. Tacrolimus (FK506)
therapeutic options is discussed in Chapter 18. is an 822 kd lipophilic immunosuppressant
Autologous serum eye drops and topical steroids belonging to the class of macrolides and isolated
are also used for management of DES but at best from a strain of Streptomyces. Both these drugs
provide short-term relief and their chronic use is act on T lymphocytes, and bind to macrophilin-12,
associated with high risk of complications. an intracellular protein. This complex inhibits
Increasingly, preparations of CsA (0.05%) are the phosphorylase enzyme, calcineurin, which
finding use as effective treatment of inflammation prevents translocation of the NFAT. The signaling
of ocular surface and moderate-to-severe dry pathway for NFAT targets specific genes in T
eye. Topical, subconjunctival, and systemic cells, including IL-2, 3, 4 and 10, IFN-γ, and
routes have been studied for CsA delivery in granulocyte-macrophage colony-stimulating
the treatment of DES. It acts by inhibiting factor. Topical tacrolimus effectively reduces
inflammation of subconjunctival and lacrimal inflammatory cells like eosinophils in the
gland, that leads to increase in tear production conjunctiva to control inflammation. In addition,
and conjunctival goblet cell density.3,4 it inhibits the release of histamine from mast cells
and reduces prostaglandin synthesis.
Atopic Keratoconjunctivitis (AKC) Tacrolimus, first used for the treatment of
atopic dermatitis, now also finds use in the
Although topical CsA is being used to provide treatment of atopic blepharoconjunctivitis and
clinical and symptomatic relief in AKC, the other severe ocular inflammatory conditions such
basis of this therapy is still under investigation. as Behcet’s disease and uveitis in the dose range
Limited preliminary data from controlled clinical of 1–2 mg/day. Tacrolimus ointment provides
trials indicates that topical CsA treatment may be therapeutic relief in atopic lid eczema without
efficacious and safe and may help to reduce use any serious side-effects. It offers the advantage of
of topical steroids in cases with steroid-dependent being more effective than CsA or corticosteroids
or resistant AKC. with less likelihood of side-effects.
Pimecrolimus (Elidel ® , 1%), sirolimus, INTERFERONS
voclosporin are some of the other calcineurin
inhibitors that are fast replacing corticosteroids IFNs are natural multifunctional proteins
for the management of inflammatory conditions that belong to the cytokine family and are
of the eye (Table 15.1). responsible for the innate immunity in humans.
Table 15.1 Immunodulators for ophthalmic use
S No. Drug Trade name Formulation/dosage Indication

1. Cyclosporine Restasias® Ophthalmic emulsion Keratoconjunctivitis sicca
0.05%
2. Tacrolimus Protopic® Ointment 0.03% Vernal keratoconjunctivitis
Ointment 0.1% Uveitis
Atopic keratoconjunctivitis
Postoperative management
of trabeculectomy
Management of graft rejection
Atopic eyelid disease
3. Pimecrolimus Elidel® Suspension 0.3% Severe keratoconjunctivitis
Suspension 1.0% sicca
4. Voclosporin LX214 Nanomicelle 0.02% Dry eye syndrome
Nanomicelle 0.2% Uveitis (phase II/III)
5. Sirolimus DE109 Liquid formulation— Uveitis (phase I)
Subconjunctival injection Diabetic macular edema
Intravitreal injection (phase II)
6. Azathioprine Imunran® Oral Behçet’s disease
Multifocal choroiditis
7. Methotrexate Rheumatrex® Oral Mild to moderate scleritis,
Folex® vasculitis
Mexate®
Trexall®
Abitrexate®
8. Mycophenolate Cellcept® Capsule 250 mg, tablet To prevent organ transplant
Mofetil 500 mg, suspension, rejection
injection
9. Infliximab, Remicade® Intravenous Under investigation for
Chimeric human- serious sight-threatening
murine antibody uveitis7
to TNF
10. Daclizumab, Zenapax® Intravenous Under investigation for
humanized ophthalmic inflammatory
monoclonal disorders8
antibody to IL-2
receptor
11. Anakinra, Kineret® 100 mg/day, Under investigation (phase
IL-1 receptor subcutaneous I/II) for Behcet’s disease,
antagonist uveitis9
12. Interferon Human Recombinant 6 million units, Viral keratitis
IFNa2a IFNa2a subcutaneous Vernal keratoconjunctivitis
Behcet’s disease10
Type I IFNs are produced by almost every cell tabolites, biologics and IFN that are marketed or
in the body and impart resistance to host cells currently under investigation are summarized in
against viral infection. On the basis of their table 15.1 and also find detailed discussion in
amino acid sequence they may be classified other chapters in this book.
as alpha, beta, gamma IFN. Type II IFNs are
specifically produced by Natural Killer cells
and T-lymphocytes and are responsible for their REFERENCES
cytotoxic and anti-proliferative properties. 1. Kari O, Saari MK. Updates in the treatment
of ocular allergies. J Asthma Allergy. 2010;3:
Mechanism of Action 149–58.
2. Sall K, Stevenson OD, Mundorf TK, Reis BL.
Interferons are characteristic products of the host Two multicenter randomized studies of the
cells but function non-specifically against various efficacy and safety of cyclosporine ophthalmic.
viruses by inhibiting their replication. IFN bind emulsion in moderate to severe dry eye disease.
to cell surface proteins to initiate intracellular Ophthalmology. 2000;107(4):631–9.
signalling pathways resulting in induction of 3. Wilson SE and Perry HD. Long-term resolution of
chronic dry eye symptoms and signs after topical
protein kinases and phosphorylation of protein
cyclosporine treatment. Ophthalmology. 2007;
synthesis factors. In addition, enzyme-2′, 5′ 114(1):76–9.
oligoadenylate synthetase is also activated, 4. Yavuz B, Pehlivan SB, Unlu N. An overview on
which in turn activates IFN-specific RNAase. dry eye treatment: approaches for cyclosporin a
This enzyme can cleave viral RNA and inhibit delivery. The Scientific Journal 2012; Article ID
viral replication. Based on this mechanism, IFNs 194848. doi: 10.1100/2012/19848.
have been implicated with anti-proliferative, 5. Stubiger N, Winterhalter S, Pleyer U, et al.
immunomodulatory and anti-angiogenic Effects and side-effects of interferon therapy in
ophthalmology. Ophthalmology. 2011;108(3):
properties and are employed for anti-neoplastic, 204–12.
anti-infective, anti-inflammatory and anti-fibrotic 6. Hayasaka S, Nagaki Y, Matsumoto M, et
uses in ophthalmology practice. al. Interferon associated retinopathy. Br J
Ophthalmol. 1998;82: 323–5.
Adverse Effects 7. Lindstedt EW, Baarsma GS, Kuijpers RWAM,
van Hagen PM. Anti-TNF-a therapy for sight
The most common adverse effects associated threatening uveitis. Br J Ophthalmol. 2005;
with systemic IFN therapy are flu-like 89:533–6.
symptoms, depression, suicidal tendencies and 8. Papaliodis GN, Chu D, Foster CS. Treatment of
ocular inflammatory disorders with daclizumab.
increase in liver enzymes.5 On topical ocular
Ophthalmology. 2003;110(4):786–9.
administration, vision loss, retinopathy and 9. http://clinicaltrials.gov/show/NCT01441076
retinal hemorrhage, ischemic optic neuropathy 10. Gantyala SP, Shekhar H, Vanathi M, Sinha R,
have been reported.6 Titiyal JS. Interferons in ophthalmology current
Various immunomodulators including status and advancing trend. Delhi Journal of
calcineurin inhibitors, corticosteroids, antime Ophthalmology. 2013;23(4):295–7.
ChapteR 16
Antiglaucoma Drugs
Glaucoma is an optic neuropathy characterized innervate the ocular structures. The details of
by structural and functional changes in the sympathetic and parasympathetic pathways
optic disc. The pathophysiology of glaucoma is are presented in Chapter 1. ACh is the neuro
multifactorial and involvement of several risk transmitter at both the sympathetic and
factors has been described. However, currently the parasympathetic preganglionic sites. Most
management of glaucoma primarily aims to lower postganglionic parasympathetic fibers are also
intraocular pressure (IOP), which is then expected cholinergic (secrete ACh) except some that utilize
to arrest the retinal ganglion cell apoptosis. IOP nitric oxide or peptides for neurotransmission.
lowering can be achieved by reducing the rate Most postganglionic sympathetic fibers are
of aqueous humor production, improving its noradrenergic (secrete norepinephrine) but those
outflow or both. The groups of pharmacological supplying sweat glands are cholinergic and the
agents used as IOP lowering agents include the ones supplying renal vascular smooth muscles
following: are dopaminergic (secrete dopamine).
1. Cholinomimetic drugs
2. Sympathomimetics and sympathetic blockers Acetylcholine
3. Carbonic anhydrase inhibitors
4. Prostaglandin analogs ACh is synthesized in the cytoplasm of the
5. Systemic hyperosmotic agents cholinergic nerves from acetyl-CoA and choline
and requires presence of the enzyme, choline
acetyltransferase (ChAT). Acetyl-CoA comes from
CHOLINOMIMETIC DRUGS mitochondria in the cell and choline is transported
Cholinomimetic drugs were the first ones used from outside the cell by a sodium-dependent
in the treatment of glaucoma. These drugs carrier. ACh once synthesized is transported into
mimic the action of acetylcholine (ACh) either the vesicles using a transporter. Action potential
because they bind directly with ACh receptors triggers the influx of Ca2+ into the nerve terminal.
and activate them or they inhibit the enzyme Increased intracellular Ca2+ destabilizes the ACh
acetylcholinesterase (AChE), which is responsible containing vesicles, which move towards the
for degradation of ACh to inactive metabolites. surface and fuse with the nerve membrane to
release their contents into the synapse. The process
of release of ACh is blocked by botulinum toxin.
Neurotransmission in Eye Released ACh acts on the cholinergic receptors
Both the sympathetic and parasympathetic and is eventually inactivated by AChE, which
components of autonomic nervous system splits it into choline and acetate (Fig. 16.1). Most
Antiglaucoma Drugs 211
receptors and their distribution are shown in
Table 16.1.
The circular muscle of iris, ciliary muscle
and lacrimal glands consist of M3 muscarinic
receptors. Stimulation of muscarinic receptors
in the circular muscle of iris results in pupillary
constriction. Ciliary muscle contraction causes
relaxation of suspensory ligaments of lens,
which makes the lens more convex and eye gets
accommodated for near vision, an effect known
as spasm of accommodation. Ciliary muscle
contraction and pupillary constriction widen the
angle of eye and pull the scleral spur so as to open
Figure 16.1 Synthesis, storage, release, degradation
and action of ach on presynaptic and postsynaptic
the canal of Schlemm more widely. This action
neurons facilitates outflow of aqueous humor. Better
of the cholinergic synapses are richly supplied aqueous humor drainage helps to lower the IOP.
with AChE. AChE is also present in other tissues
like red blood cells. Another cholinesterase, Cholinomimetic Drugs:
butryl or pseudocholinesterase, which has a low Classification
specificity for ACh is present in plasma, liver and
The cholinergic drugs used in the treatment of
many other tissues.
glaucoma are classified in two categories based
on their mechanism of action:
Cholinergic receptors
1. Direct-acting cholinergic drugs: Pilocarpine,
Cholinergic receptors are of two types—nicotinic carbachol
and muscarinic. The subtypes of these cholinergic 2. Indirect-acting cholinergic drugs: Ecothiophate
Table 16.1 Cholinergic receptors—types, subtypes, distribution and intracellular signaling
Receptor Nicotinic Muscarinic

types
Receptor NM NN M1 M2 M3
sub-types
Distribution Neuromuscular Autonomic Sympathetic Myocardial and Glands
junctions ganglia brain ganglia smooth muscle cells
Visceral and
Gastric parietal Presynaptically in vascular
cells peripheral and central smooth
neurons muscles,
Cerebral cortex
Endothelium
Intracellular Depolarization Depolarization G-protein Opening of K+ channel G-protein
signaling of postsynaptic of postsynaptic activation → → inhibition of activation →
membrane membrane Formation of adenylyl cyclase Formation of
subsequent to subsequent to IP3+DAG → IP3+DAG →
opening of Na+, opening of Na+, increased increased
K+ channels K+ channels intracellular intracellular
calcium calcium
Pilocarpine Therapeutic uses

Pilocarpine is an alkaloid derived from the Among the cholinomimetic drugs, pilocarpine
leaves of tropical American shrubs of the genus is the most useful antiglaucoma drug in the
Pilocarpus. It is a direct-acting cholinomimetic management of primary open-angle glaucoma
drug, i.e. it directly interacts with muscarinic (POAG), acute angle-closure glaucoma and
receptors and produces actions similar to ACh. many secondary glaucomas. During the acute
Both the central and peripheral muscarinic attack of angle-closure glaucoma, the sphincter
receptors are stimulated. The ocular responses muscle of iris is often ischemic due to high IOP.
to pilocarpine like ACh include miosis, spasm Pilocarpine instillation under such conditions may
of accommodation and reduction in IOP. 1 be ineffective and use of systemic IOP lowering
Pilocarpine reduces IOP in both the normal and drugs is indicated. Use of pilocarpine has also
glaucomatous eyes by about 15%. 2 It can be been described during laser iridotomy to facilitate
used in combination with other IOP lowering stretching of iris.4
drugs. Pilocarpine hydrochloride 0.25–10% and
pilocarpine nitrate 1–4% are available in solution. Adverse Effects
Use of higher concentration generally does not
yield additional advantage; however, patients Ocular adverse effects
with pigmented iris may respond poorly and
require higher concentrations. Pilocarpine is also The ocular adverse effects of pilocarpine are
available in 4% concentration in gel form. Other significant especially on long-term use and
preparations of pilocarpine include ocusert Pilo- require discontinuation of therapy in large
20 and 40. These are sustained release membrane number of patients. The troublesome adverse
bound dosage forms, which release pilocarpine at effects are primarily attributed to ciliary spasm
the rate of 20 and 40 µg/hour, respectively. and miosis. Ciliary spasm lasts for 2–3 hours
The frequency of instillation with pilocarpine after instillation and is especially troublesome
solutions is usually 4 times a day but if the for patients younger than 40 years of age. Older
nasolacrimal occlusion is performed, good IOP patients generally tolerate it better as the ciliary
control can be maintained with twice a day muscle contractility reduces with age.5 Miosis
instillations. 3 Pilocarpine gel 4% is used by interferes with vision especially in patients
applying ½ inch ribbon in the lower conjunctival with nuclear or subcapsular cataract and under
sac once a day at bedtime. Ocuserts offer the dim illumination. Long-term use of pilocarpine
advantage of reduced dosing frequency. The peak causes loss of tone of radial muscle of iris
IOP lowering appears 2 hours after insertion and and fibrosis of sphincter muscle resulting in
lasts for about 7 days. The hypotensive effect of permanent miosis.6 The actions of pilocarpine
ocusert pilo-20 equals that of pilocarpine solution also cause forward displacement of iris-lens
1–2%, four times a day and the effect of ocusert diaphragm and, therefore, long-term instillation
pilo-40 is equivalent to pilocarpine solution 2–4%, of pilocarpine can cause pupillary block and
four times a day. Despite the benefit of reduced subsequent angle closure.7 Forward displacement
frequency of dosing, ocusert is rarely used in of iris-lens diaphragm also predisposes to retinal
practice because of its several disadvantages. The detachment.8 Long-term use of pilocarpine is also
main problems of using ocusert are difficulties of associated with cataract development.9 Periodic
insertion and removal, possibility of membrane examination of retina and optic disc with pupillary
rupture causing sudden release of excessive dilatation after discontinuation of pilocarpine
quantity of drug, foreign body sensation, unnoticed helps not only in early detection of drug-related
loss of the device and high cost. adverse effects but also helps to avoid some of
the adverse effects due to sustained pilocarpine implantation to induce miosis and achieve better
action such as permanent miosis. IOP control postoperatively. It can also be used
Other adverse effects of pilocarpine include in primary and secondary glaucomas but due to
ciliary and conjunctival congestion, frontal its more severe ocular adverse effects, pilocarpine
headache and ocular and periorbital pain. These is a preferred choice among cholinergic drugs.
effects are short-lasting and disappear with
continued therapy. Adverse effects and contraindications
Ocular adverse effects of carbachol are similar to
Systemic adverse effects
pilocarpine but are more severe. Systemic adverse
The systemic adverse effects of pilocarpine are effects and contraindications are also the same as
rare but with the use of high concentration, those of pilocarpine.
systemic symptoms such as salivation, lacrimation,
diarrhea and bronchospasm may appear. Ecothiophate
Ecothiophate is an indirect-acting cholinomimetic
Contraindications drug. It acts by inhibiting the enzyme AChE,
Use of pilocarpine is contraindicated in patients thereby increasing the concentration of
younger than 40 years of age and in those with endogenous ACh. The inhibitors of AChE
acute angle-closure glaucoma, cataract or history belong to two categories—reversible inhibitors
of retinal detachment. Patients with myopia are at and irreversible inhibitors. Reversible inhibitors
high risk of retinal detachment. Pilocarpine should of AChE, like physostigmine, form a complex
also be avoided in patients with neovascular with AChE, which dissociates quickly to make
and uveitic glaucoma and those with history of the enzyme free for its action on ACh. Thus
bronchial asthma. the action of reversible AChE inhibitors is
short-lasting. Irreversible AChE inhibitors like
Carbachol ecothiophate make a stable complex with AChE,
Carbachol, like pilocarpine, is a direct acting which dissociates very slowly and, therefore,
cholinergic drug with same mechanism of such drugs have long duration of action. The
action. However, its duration of action is longer effects of ecothiophate on iris, ciliary body and
than pilocarpine as it is completely resistant IOP are same as that of pilocarpine. After topical
to hydrolysis by AChE. It requires 8 hourly application, miosis begins in 10–30 minutes and
instillations but with nasolacrimal occlusion lasts for 1–4 weeks. Maximum IOP reduction is
good IOP control can be achieved with twice achieved at 24 hours and lasts for days or weeks.
a day instillation. Carbachol chloride solution Ecothiophate iodide is available for topical
is available for topical use in the concentration instillation in concentration range of 0.03–0.25%.
range of 0.75–3%. Preservative-free carbachol It is supplied in powder form, which requires
solution is available for intracameral use in 0.1% reconstitution and storage in refrigerator for
concentration, of which 0.5 mL is applied by stability. Despite its potent action, it is not used
gentle irrigation postoperatively. in glaucoma due to its severe adverse effects and
narrow therapeutic index.
Therapeutic uses
The most common use of carbachol is by
intracameral injection in patients undergoing Development of cataract is the major ocular
phacoemulsification and posterior chamber lens complication of ecothiophate. Other ocular
adverse effects of ecothiophate are similar to supplied by sympathetic nerves. Details of
pilocarpine but are more severe. Significant sympathetic innervations of eye are described in
systemic absorption of ecothiophate can cause Chapter 1.
serious toxicity such as intestinal cramps,
hypotension, cardiac arrest, respiratory failure Catecholamines
and CNS symptoms. In patients already receiving
anticholinesterases, such as in myasthenia gravis, Biosynthesis of catecholamines utilizes dietary
are likely to have serious systemic toxicity. amino acid L-phenylalanine, which gets oxidized
Ecothiophate can prolong the duration of action to L-tyrosine in liver. Circulating L-tyrosine is
of succinylcholine by lowering the concentration actively taken up by adrenergic neurons. In the
of plasma pseudocholinesterase, which is required neuronal cytoplasm L-tyrosine is hydroxylated
for the breakdown of succinylcholine. Therefore, to L-dopa by the enzyme tyrosine hydroxylase.
patients receiving general anesthesia with This is a rate-limiting step in the synthesis of
succinylcholine as muscle relaxant can develop catecholamines and is inhibited by negative
respiratory paralysis. The patients exposed to feedback in the presence of sufficient quantities
insecticides may show additive effects causing of catecholamine in the nerve terminal. L-dopa
systemic toxicity. is then carboxylated to dopamine in the presence
The contraindications for the use of ecothi of the enzyme L-amino acid decarboxylase.
ophate are same as those of pilocarpine. Drug Dopamine is transported inside the storage
requires discontinuation several weeks before vesicles where it undergoes further conversion to
the general anesthesia with succinylcholine is norepinephrine by dopamine –β-hydroxylase. In
planned. Similar discontinuation is also required the adrenal medulla, norepinephrine is converted
before intraocular surgery to allow time for to epinephrine in the presence of the enzyme
conjunctival and ciliary congestion to subside phenylethanolamine-N-methyltransferase.
before surgery. Catecholamines are stored in storage vesicles
complexed with ATP. An action potential triggers
the inflow of Ca++ and causes vesicle disruption
SYMPATHOMIMETICS AND and release of catecholamines. The action of
SYMPATHETIC BLOCKERS adrenergic neurotransmitters is terminated
primarily by neuronal re-uptake and remaining
Adrenergic agonists are the drugs that act is metabolized by the enzymes monoamine
by stimulating sympathetic receptor actions oxidase (MAO) or catechol-O-methyl transferase
or they mimic the action of catecholamines (COMT) (Fig 16.2).
(sympathetic neurotransmitters). Sympathetic
blockers are antagonists at sympathetic receptors
Sympathetic receptors
and act by blocking sympathetic transmission.
Three endogenous catecholamines include Released norepinephrine and epinephrine act
norepinephrine, epinephrine and dopamine. on sympathetic receptors, which belong to two
Norepinephrine is the major neurotransmitter at main categories: alpha (α) receptors and beta (β)
postganglionic sympathetic sites. Epinephrine receptors. Alpha receptors are of two subtypes i.e.
is secreted by adrenal medulla. Dopamine is the α1 and α2 whereas β receptors are of three subtypes
sympathetic neurotransmitter at various sites in i.e. β1, β2 and β3. The distribution of α and β
brain and renal blood vessels (Fig. 16.2). receptors is shown in Table 16.2. All sympathetic
Intraocular sympathetic innervation is receptors are G-protein linked.
primarily restricted to radial muscles of iris. α 1 receptors are predominantly located
Circular muscles of iris do not receive sympathetic postsynaptically in vascular smooth muscles.
supply. The smooth muscles of eyelids are also The catecholamine actions through postsynaptic
Figure 16.2 Synthesis, storage, release, degradation and action of

norepinephrine on presynaptic and postsynaptic neurons
α1 receptors are mediated through formation of be present in ciliary body and affect aqueous
IP3 and DAG leading to increased intracellular humor production. Therefore, reduced β receptor
calcium and muscle contraction. α2 receptors are activity such as in the presence of β-blockers
predominantly presynaptic and mediate their reduces aqueous humor production and IOP.
action through inhibition of adenylyl cyclase Presynaptic α 2 receptor activation reduces
causing reduced cellular cAMP. This action catecholamine release and henceforth reduces
leads to decreased catecholamine release from its availability and stimulation of postsynaptic
presynaptic nerves. The postsynaptic β receptors α 2 and β 2 receptors. Besides aqueous humor
stimulate adenylyl cyclase and increase cellular production, outflow facility and arterial and
cAMP levels. venous pressure are also modulated by α 2
In eye, α2 receptors have been identified on receptor activity.
the presynaptic sympathetic nerve terminals Antiglaucoma drugs acting through sympa
and postsynaptically in the ciliary body. β 2 thetic receptors are classified in two categories:
receptors are present postsynaptically in ciliary 1. Sympathetic agonists
body and upon activation increase the aqueous a. α2 Agonists: apraclonidine, brimonidine,
humor production. β1 receptors are also said to dipivefrin
Table 16.2 Sympathetic receptor subtypes, distribution and intracellular signaling mechanisms
Receptor Adrenergic receptors

types
Receptor a1 a2 b1 b2 b3
sub-types
Distribution Vascular Presynaptic on Postsynaptic in Postsynaptic Adipocytes
smooth sympathetic heart, kidney in bronchi,
muscles, postganglionic blood vessels
salivary glands, neurons and in skeletal
bronchi, uterus, cholinergic muscles,
radial muscle of terminals in gut coronaries,
iris, liver cells uterus, GIT
Brain
Cardiac muscle
Intracell- G-protein G-protein G-protein G-protein G-protein
ular signaling activation → activation activation → activation → activation →
Formation of → inhibition stimulation of stimulation stimulation of
IP3+DAG → of adenylyl adenylyl cyclase of adenylyl adenylyl cyclase
increased cyclase → → increased cyclase → → increased cyclic
intracellular decreased cyclic AMP increased cyclic AMP
calcium cyclic AMP AMP
Activation of
cardiac Gi
under some
conditions
2. Sympathetic blockers Therapeutic Uses

a. Non-selective β-blockers: Timolol,
levobunolol, metipranolol, carteolol Apraclonidine hydrochloride is available in 0.5
b. β1-selective blocker: Betaxolol and 1% concentrations. Its 0.5% concentration
is used three times a day as short-term add on
therapy in patients inadequately controlled with
Apraclonidine
other maximally tolerated medications. Long-
Apraclonidine is a relatively selective α2 agon term use is not satisfactory due to development
ist and reduces IOP in both the normal and of tachyphylaxis. Primary as well as secondary
glaucomatous eyes. Following instillation, the glaucomas respond equally but congenital
effect appears within 1 hour, reaches peak in about glaucoma responds poorly. Apraclonidine 1%
3–5 hours and lasts for 12 hours. An average of is used to control postoperative IOP elevation
20% reduction is achieved with both 0.5% and in patients undergoing anterior segment laser
1.0% solutions.10 This initial effect on IOP is surgery and for short-term IOP control in open-
primarily due to reduced aqueous production.11 angle glaucoma before filtration procedure.
After continued treatment for more than 8 days
the IOP reduction is primarily due to improved
uveoscleral outflow of aqueous humor.12 With
long-term treatment, the ocular hypotensive effect Conjunctival blanching, eyelid retraction and
of apraclonidine reduces due to development of mydriasis are the most common side-effects
tachyphylaxis. The age, race and color of iris do due to α1 receptor activation. Instillation may
not affect the IOP lowering by apraclonidine. be associated with discomfort, burning, itching
and dryness. Ocular hypersensitivity reaction Adverse Effects and Contraindications
can appear specially on long-term use. Systemic
absorption is poor because of the poor lipophilicity The most common ocular adverse effects include
hyperemia, burning, stinging and foreign body
of the drug and systemic adverse effects, therefore,
sensation. Ocular allergy may manifest as lid
are dose-dependent. Common systemic adverse
edema, conjunctivitis and conjunctival fol
effects include dry mouth, dry nose, headache,
licles. Incidence of ocular allergy with brim
lethargy, chest heaviness, shortness of breath and
onidine is much lower as compared to that with
taste abnormalities. apraclonidine. Systemic adverse effects and
Use of apraclonidine is contraindicated in contraindications are similar to apraclonidine.
patient on monoamine oxidase inhibitors and
those with allergy to clonidine. A cautious use is
Dipivefrin
indicated in patients with hypertension or severe
cardiovascular disease. Dipivefrin is a prodrug, which metabolizes to
epinephrine and provides enhanced corneal
permeability compared to epinephrine. It acts
Brimonidine
by stimulating α- and/or β2-adrenergic receptors
Brimonidine is a highly selective α2 agonist and resulting in improved uveoscleral outflow.
like apraclonidine reduces IOP in both the normal Trabecular outflow is affected to a lesser extent.
and glaucomatous eyes. Reduction of IOP by After topical application, the IOP lowering effect
brimonidine occurs by the similar mechanism as appears in 30 minutes, reaches peak in 1 hour and
apraclonidine, i.e. reduced aqueous production persists for 12 hours or more.
on initial use and improved uveoscleral outflow
on prolonged use. Additionally, brimonidine has Therapeutic Uses
been shown to provide neuroprotective effect Dipivefrin hydrochloride is indicated as initial
and protects the retinal ganglion cells from therapy for controlling IOP in chronic open-angle
apoptosis.13,14 Brimonidine binds with ocular glaucoma. It is administered twice daily and
melanin, which prolongs its half-life. The peak reduces IOP by 20–24% in 3–5 months.
IOP lowering by brimonidine appears 2 hours Therapeutic response to dipivefrin ophthalmic
post-instillation and lasts for 12 hours. A mean solution twice daily is somewhat less than 2%
IOP reduction by 6.5 mm Hg from baseline has epinephrine twice daily. Controlled studies
been reported with 0.2% concentration.15 The showed statistically significant differences in
IOP lowering effect of 0.2% brimonidine is IOP lowering in response to dipivefrin 0.1% and
comparable to 0.5% timolol and is higher than 2% epinephrine. In controlled studies involving
0.5% betaxolol.16,17 patients with a history of epinephrine intolerance,
only 3% patients treated with dipivefrin
Therapeutic Uses ophthalmic solution exhibited intolerance, while
55% of those treated with epinephrine again
Brimonidine tartrate 1%, two or three times a developed intolerance.
day is used topically for the treatment of open- Therapeutic response to dipivefrin twice
angle glaucoma and ocular hypertension. It is daily therapy is comparable to 2% pilocarpine
also effective in attenuating the IOP spiking after four times daily. Controlled clinical studies
laser trabeculoplasty. Like apraclonidine, it can be comparing dipivefrin ophthalmic solution
used as add on or replacement therapy in patients and 2% pilocarpine, showed no statistically
showing inadequate control with maximally significant differences in the maintenance of
tolerated medical therapy. IOP levels. Dipivefrin does not produce miosis
or accommodative spasm. Night blindness often is also effective in the prophylactic treatment of
associated with miotic agents is not associated IOP elevation due to laser iridotomy or posterior
with dipivefrin therapy. Patients with cataract capsulotomy and cataract surgery.
avoid the inability to see around lenticular
opacities caused by constricted pupil. Adverse effects and contraindications
Ocular irritation on instillation is not seen
frequently, however, local allergic reaction
Photosensitivity, conjunctival hyperemia and can occur. Allergy manifests as lid edema and
blephroconjunctivitis are the common ocular conjunctivitis and may require replacement
adverse effects. Systemic adverse effects such by another beta blocker or a drug from other
as tachycardia, arrhythmias and hypertension pharmacological group. Due to the membrane
are rare. Use of dipivefrin is contraindicated in stabilizing properties, beta-blockers produce
patients with angle-closure glaucoma or in patients corneal anesthesia. However, the anesthetic effect
predisposed to angle closure. Use of dipivefrin of timolol is least among all beta blockers and is
requires caution in patients with cardiac diseases. not significant clinically. Other ocular adverse
effects of timolol include dry eye symptoms and
Timolol sometimes superficial punctate keratitis.
Significant systemic absorption of timolol can
Timolol is a non-selective β-blocker without give rise to bradycardia, systemic hypotension,
intrinsic sympathomimetic activity. It acts by heart block, bronchospasm, diarrhea, lethargy,
reducing aqueous humor production and has no amnesia, emotional instability and sexual
effect on aqueous outflow. The peak IOP lowering dysfunction. Topical timolol can adversely
appears in about 1 hour post-instillation and lasts affect the carbohydrate and lipid metabolism but
for 12 hours. A twice daily instillation is often has not been associated with increased risk of
recommended, however, once daily use has also coronary artery disease. The systemic effects are
shown similar efficacy. An IOP reduction of more likely in elderly due to coexisting systemic
more than 30% has been reported.18 The maximal illnesses and non-compliance.
efficacy of timolol in concentrations ranging from Timolol is contraindicated in patients with
0.1–0.5% is similar. But patients with dark iris may bronchial asthma, chronic obstructive pulmonary
require higher concentration to achieve the same disease, bradycardia, congestive cardiac failure,
effect because of the melanin binding of the drug. heart block and sensitivity to drug. Topical
The other eye effect due to systemic absorption timolol can mask the symptoms of thyrotoxicosis
is significant. The IOP lowering effect of timolol and hypoglycemia and, therefore, should be
is additive with other IOP lowering drugs. On used with caution in patients with diseases like
long-term use 5–10% of the patients per year have diabetes mellitus. In patients already on systemic
been reported to develop tolerance and require beta-blocker therapy, drugs from other classes
additional medications.19 On discontinuation of are preferred. Combination of two beta blockers
therapy, the IOP lowering effect of timolol lasts for needs to be avoided as it does not increase the
up to 2 weeks or longer in patients with dark iris.20 effectiveness of the therapy but risk of systemic
adverse effects increases.
Therapeutic Uses
Timolol maleate and timolol hemihydrate are Levobunolol
available for topical use in concentration of 0.25 Levobunolol, like timolol is a non-selective
and 0.5%. It is used in the treatment of POAG, β blocker without intrinsic sympathomimetic
ocular hypertension and secondary glaucomas. It activity but unlike timolol it has no local
anesthetic activity. The mechanism of IOP Therapeutic uses
lowering by levobunolol is the same as that
of timolol. Levobunolol metabolizes to an Racemic betaxolol hydrochloride (0.25%)
equipotent metabolite and has efficacy similar suspension is used twice a day topically in the
to timolol. The IOP reduction following topical treatment of ocular hypertension and open-angle
application of levobunolol is similar to timolol glaucoma. Due to its relatively specific β1 effects
in terms of peak effect as well as the duration of it is safer in patients with coexisting pulmonary
action. Both the 0.25 and 0.5% concentrations are disease, however, its efficacy is less than the
equally effective and once daily instillations are as non-selective β-blockers. The levo isomer of
effective as twice daily. Development of tolerance betaxolol is used as 0.5% suspension and has
on chronic use is also the same as with timolol. efficacy similar to timolol maleate 0.5%. It is
also less effective in preventing IOP elevations
Therapeutic Uses after cataract surgery and is, therefore, not the
agent of choice.
Levobunolol hydrochloride is available in
0.25 and 0.5% concentrations. It is used in the
treatment of POAG and ocular hypertension.
Like timolol it is also effective in the prophylactic Ocular irritation and stinging due to instillation
treatment of IOP elevation due to laser iridotomy is much less with 0.25% concentration but
or posterior capsulotomy and cataract surgery. is significant with 0.5% concentration. The
effects of systemic β-blockade are significantly
Adverse Effects and Contraindications less than non-selective β-blockers, however,
the IOP control is poorer. The use of betaxolol
The ocular adverse effects of levobunolol are
is contraindicated in patients with sinus
similar to timolol but it does not produce corneal
bradycardia, heart block, congestive cardiac
anesthesia and dry eye symptoms. It can produce
failure and cardiogenic shock. Although the
allergic blephroconjunctivitis but in patients
drug has relatively less effects on pulmonary
showing allergy to timolol it can be used as
functions it should be used with caution in
replacement.
The adverse effects due to its systemic patients with bronchial asthma and chronic
absorption and contraindications are same as obstructive pulmonary disease. The drug is
those with timolol. also contraindicated for use in patients with
hypersensitivity to any of its components.
Betaxolol
Metipranolol
Betaxolol is a β-blocker with relative specificity Metipranolol is a non-selective β-blocker with no
for β1 receptors. It reduces IOP by reducing the local anesthetic and intrinsic sympathomimetic
aqueous humor formation, however, its efficacy activity. Like timolol it acts by reducing the
in reducing IOP is lower than that of timolol and aqueous humor formation and its efficacy in
levobunolol.21 Additionally, betaxolol has calcium
reducing IOP is comparable to other non-selective
channel blocking action in ocular vasculature as
β-blockers.
well as retinal ganglion cells. Blockade of calcium
channels causes vasorelaxation and improves
retinal blood flow.22 In the retinal ganglion cells
Therapeutic Uses
betaxolol prevents glutamate-mediated calcium Racemic metipranolol hydrochloride 0.1–0.6%
influx and cell death. 23 Thus, betaxolol may is used twice daily in the treatment of ocular
possess additional neuroprotective properties. hypertension and glaucoma.
Adverse Effects and Contraindications acid (H2CO3), which dissociates quickly into H+
and HCO3–. The sodium ions (Na+), which are the
Topical instillation is associated with allergic main cations, are transported into the cells either
blepharoconjunctivitis, uveitis and periorbital by diffusion or by Na+-H+ exchanger.
dermatitis. The ocular side-effects occur more Na+-K+- ATPase transports Na+ accompanied
often with the use of higher concentrations. with HCO3– into the lateral intercellular space.
The adverse effects due to its systemic absor Some chloride ions (Cl–) are also transported
ption and contraindications are same as those into the lateral intercellular space, however,
with timolol. mechanism of their transport is not known. This
movement of ions in the lateral intercellular
Carteolol space creates hypertonicity and attracts water by
Carteolol is a non-selective β-blocker but possesses osmosis. As there are tight junctions between the
local anesthetic and intrinsic sympathomimetic ciliary epithelial cells on stromal side, the newly
activity. It reduces IOP by reducing aqueous formed fluid moves into the posterior chamber.
humor formation. The IOP lowering efficacy of CAIs reduce the formation of HCO 3– by
carteolol 1% is comparable to timolol 0.5%.24 inhibiting the activity of CA. Moreover, CAIs
alter the intracellular pH, which affects the
activity of Na +-K +-ATPase and transport of
Therapeutic Uses Na+ is also inhibited. Thus inhibition of CA by
Racemic carteolol hydrochloride 1% is used twice CAIs reduces aqueous humor production by
daily in the treatment of ocular hypertension and reducing transport of Na +, HCO 3– and water
glaucoma. into the intercellular spaces and subsequently to
posterior chamber. The amount of CA present
Adverse Effects and Contraindications in tissues is much higher than the physiological
requirement and, therefore, to inhibit aqueous
The ocular irritation due to 1% carteolol is humor production at least 99% of the enzyme
less than 0.5% timolol. Although the systemic in ciliary processes must be inhibited. This is
adverse effects are same as timolol, due to its easily achieved with systemic CAIs and newly
intrinsic sympathomimetic activity, effects developed topical CAIs. CAIs are classified in
on pulmonary functions and heart are less two categories:
pronounced. Contraindications for the use of
1. Systemic CAIs: Acetazolamide, Methazol
carteolol are same as those of timolol.
amide, Dichlophenamide.
2. Topical: Dorzolamide, Brinzolamide
CARBONIC ANHYDRASE INHIBITORS
Acetazolamide
Carbonic anhydrase inhibitors (CAIs) reduce the
IOP by inhibiting the enzyme carbonic anhydrase Acetazolamide is administered orally as 125
and reducing aqueous humor production. Carbonic or 250 mg tablets or 500 mg sustained release
anydrase is one of the key enzymes in aqueous capsules. The recommended dose is 250 mg 6
humor production in non-pigmented ciliary hourly or 500 mg capsule twice a day. The ocular
epithelium. hypotensive effect after oral 250 mg tablet appears
In ciliary epithelial cells bicarbonate ions in 2 hours and lasts for 6 hours. The effect of
(HCO3–), which are the main anions, are generated sustained release capsule appears in 2 hours and
in the presence of carbonic anhydrase. Carbonic lasts for 6–18 hours. Although the duration of
anhydrase catalyzes the reaction of CO2 with IOP reduction is higher with sustained release
water resulting into the formation of carbonic preparation, the magnitude of IOP reduction is less
as compared to 6-hourly tablets. Acetazolamide is are tingling and numbness in fingers, toes and
also available for intravenous use in 500 ml vial. perioral region and metallic taste. On prolonged
After intravenous administration the IOP lowering use a symptom complex characterized by malaise,
effect persists for 4 hours. fatigue, weight loss, depression, anorexia and
Acetazolamide is readily absorbed after oral loss of libido may appear.25 Oral acetazolamide
administration and attains peak plasma levels can also cause cramps, nausea and diarrhea
in 2–4 hours. Peak level with 250 mg tablet is due to gastrointestinal irritation. In kidney,
maintained for 4-6 hours but up to 10 hours with acetazolamide prevents HCO3– excretion and,
sustained release preparation. The peak levels therefore, causes alkaline urine and metabolic
achieved with sustained release are lower than that acidosis. Besides, excretion of citrate is also
with tablets. Acetazolamide is extensively bound inhibited. Low citrate and alkaline pH of urine
to plasma proteins (90–95%) and the free form favor calcium phosphate precipitation in urine.
is in unionized form, which can easily penetrate Acetazolamide can also cause blood dyscrasias
through cell membranes. It is not metabolized and such as thrombocytopenia, agranulocytosis and
is excreted unchanged in urine by tubular secretion. aplastic anemia. Myopic shift in refractive error
Because of its renal action, acetazolamide promotes may also occur.
HCO3– excretion in urine and makes it alkaline.
Alkaline pH keeps acetazolamide in ionized form Contraindications
and favors its excretion.
Acetazolamide is unsubstituted aromatic
Therapeutic Uses sulfonamide. Although, its structure significantly
differs from the antibacterial sulfonamides,
Acetazolamide is used as an add on therapy in the hypersensitivity reactions have been reported.
treatment of POAG when topical drugs provide Therefore, in patients with history of
insufficient control of IOP. In combination with hypersensitivity to sulfonamides, acetazolamide
timolol, the IOP lowering effect is additive as should be avoided. It should also be used with
both the drugs act by reducing aqueous humor caution in patients with impaired renal and
production. Timolol does not reduce nocturnal hepatic functions. In presence of renal failure the
aqueous humor production but acetazolamide drug may accumulate in plasma as it is excreted
can reduce it by 24%. Therefore, the bed-time unchanged in urine. Alkaline pH of urine caused
instillation of timolol is not required and it is by acetazolamide prevents excretion on NH4+
added to as day time instillation. Topically used and thus can significantly increase ammonia
CAIs are now preferred over acetazolamide due levels in patients with impaired hepatic function.
to low risk of adverse effects. In the treatment of Patients with diabetic nephropathy can develop
acute angle-closure glaucoma acetazolamide is serious acidosis. Acetazolamide should also
used preoperatively along with timolol. In such be avoided in patients with chronic obstructive
condition, acetazolamide can be administered pulmonary disease as the acid-base imbalance
intravenously especially if the patient is not able can precipitate acute respiratory failure. In patients
to take orally due to vomiting.
with significant outflow obstruction, CAIs are
not as useful because they act by decreasing the
Adverse Effects aqueous humor production without any effect on
Although, the incidence of adverse effects outflow. Moreover, the production reduces only by
varies with dose and formulation, intolerable 45–55%, which may not be enough to reduce IOP.
adverse effects are experienced by up to 80% Acetazolamide should also be avoided in pregnant.
of the patients and tolerability is often poor. Acetazolamide induced hypokalemia is
The most common but tolerable adverse effects exaggerated if the patient is also taking a
thiazide diuretic. Digitalis toxicity may be Therapeutic Uses
precipitated in presence of hypokalemia.
The alkalinization of urine by acetazolamide Dorzolamide 2% is used three times a day for IOP
increases tubular reabsorption of some drugs reduction in patients with ocular hypertension
like tricyclic antidepressants, quinidine and and open angle glaucoma. It can be used as
amphetamine. Consequently, the action of these monotherapy or in combination with other IOP
drugs is prolonged. Concurrent use of aspirin and lowering drugs. Topical carbonic anhydrase
acetazolamide increases serum levels of unionized inhibitors do not reduce IOP as effectively as
salicylic acid. systemic drugs, therefore, their use is limited
to management of chronic glaucoma. It is also
effective in the prophylactic treatment of IOP
Methazolamide
spiking after YAG laser capsulotomy, argon laser
M e t h a z o l a m i d e s t r u c t u r a l l y r e s e m b l e s trabeculoplasty or laser iridotomy.
acetazolamide. However, its efficacy in reducing
IOP is achieved at 100 mg dose compared to Adverse Effects and Contraindications
250 mg of acetazolamide. The peak levels of
methazolamide are maintained for 8 hours as The most common ocular adverse effects
compared to 4–6 hours with acetazolamide. following topical instillation include stinging,
The half-life of methazolamide is 14 hours as burning, foreign body sensation and blurred
compared to 5 hours of acetazolamide. vision. Dorzolamide 2% solution has a pH of
5.6 and, therefore, the local irritation is possibly
related to the acidic pH. Topical dorzolamide
Dichlophenamide
can also cause local allergic reactions involving
Dichlophenamide is also an orally administered lids and conjunctiva. Dorzolamide also inhibits
carbonic anhydrase inhibitor. Its pharmacological carbonic anhydrase II in corneal endothelium
actions are similar to acetazolamide, however, and, therefore, can cause corneal edema and
the diuresis persists even after long-term use decompensation specially in patients who have
and hypokalemia is more likely. The drug has undergone intraocular surgery.28 Although topical
clinical use limited to patients not able to tolerate dorzolamide does not cause significant systemic
acetazolamide and methazolamide. adverse effects, its concomitant administration
with systemic carbonic anhydrase inhibitors is not
Dorzolamide recommended. Safety of dorzolamide in children
and pregnant is not established. It should also
Dorzolamide is a topically administered carbonic be avoided in patients with history of allergy to
anhydrase inhibitor. It reduces the rate of aqueous sulfonamides.
humor secretion by inhibiting the isoenzyme II in
the ciliary processes. It also inhibits membrane-
bound isoenzyme IV. The effect of dorzolamide
Brinzolamide
on aqueous humor secretion is less as compared to Brinzolamide, like dorzolamide, is a topically
acetazolamide, due to incomplete inhibition of the administered carbonic anhydrase inhibitor. Its
enzyme isoforms. The peak IOP reduction occurs action on carbonic anhydrase and effect on
2 hours post-instillation. When instilled 3 times a aqueous humor secretions are same as those
day, 2% concentration produces an IOP reduction of of dorzolamide. The extent of IOP reduction is
22–26%.26 The night time aqueous humor secretion comparable to dorzolamide. It causes less ocular
is inhibited more effectively with topical carbonic irritation as compared to dorzolamide. Therapeutic
anhydrase inhibitors as compared to timolol. uses, adverse effects and contraindications for
Dorzolamide has additive effect with timolol.27 brinzolamide are same as those of dorzolamide.
PROSTAGLANDIN ANALOGS for IOP reduction in patients with normal tension

glaucoma.
Prostaglandins used topically in the treatment
of glaucoma are PGF2α analogs. Prosatglandin Adverse Effects and Contraindications
analogs lower the IOP by increasing the aqueous
outflow exclusively through uveoscleral pathway.29 Latanoprost on continued use causes increased
The action of PGF2α analogs is mediated through melanin accumulation in the iridial melanocytes,
activation of prostanoid FP receptors, which are which is evidenced by darkening or iris color.
located in the ciliary muscle, circular muscle of This change is observed in 5–20% of patients
iris and aqueous outflow pathways. FP receptor and those with mixed color irides. The change is
stimulation is associated with substantial permanent and takes 4 weeks to several months
extracellular matrix remodeling and reduced to appear. Skin of eyelids can also show increased
collagen in the ciliary muscle and adjacent sclera pigmentation. Prolonged latanoprost treatment
secondary to activation of matrix degrading also stimulates cell division and growth leading
metalloproteinases. This action leads to reduced to hypertrichosis. The eyelashes become thick,
resistance to the outflow of aqueous humor.30,31 long and dark. Eyelashes can also grow in areas
adjoining the normal eyelash distribution. The
Latanoprost change is especially noticeable in patients using
latanoprost unilaterally. Conjunctival hyperemia
Latanoprost was the first prostagladin used has been reported in approximately one-third of
in the treatment of glaucoma. The peak IOP the treated patients. Allergy to latanoprost may
lowering effect of latanoprost appears 8 hours require discontinuation of treatment. Punctate
post-instillation and persists for 12–24 hours. epithelial corneal erosions and pseudodendritic
Therefore, only once a day instillation is required. corneal lesions resembling herpes simplex virus
When instilled at bedtime, it provides effective (HSV) infection have been reported in patients
IOP control throughout the day with minimal using latanoprost. Such changes can be attributed
diurnal variations. Once a day latanoprost
to the preservative used in the formulation rather
reduces IOP by about 27%, which is higher
than the latanoprost itself. Being a prostaglandin,
than the IOP lowering by timolol 0.5% twice a
latanoprost has been suggested to increase blood
day.32,33 Thus the patients showing inadequate
aqueous and blood-retinal barrier permeability
IOP control with timolol monotherapy can be
switched to latanoprost monotherapy to achieve leading to uveitis and cystoid macular edema
higher IOP reduction. Moreover, due to its unique (CME) respectively. However, such associations
mechanism of action, it has additive effect when have not been confirmed in patients on long-
used in conjunction with other IOP lowering term latanoprost treatment. Latanoprost has no
drugs such as timolol, pilocarpine, acetazolamide. significant systemic adverse effects.
Latanoprost, by virtue of its higher efficacy, once Use of latanoprost is contraindicated in
daily dosing, absence of systemic toxicity and patients with history of HSV keratitis, uveitis,
excellent tolerability, is now considered as the first CME, pervious intraocular surgery especially
line drug in the treatment of glaucoma. with vitreous loss and diabetes mellitus. The
risk of iris pigmentation and hypertrichosis must
Therapeutic Uses be explained especially to patients intending
unilateral use.
Latanoprost 0.005% is used once a day in the
evening or bedtime in the treatment of ocular
Unoprostone
hypertension and POAG. The IOP lowering by
latanoprost in pigmentary glaucoma is higher Unoprostone is a derivative of PGF2α metabolite.
than that caused by timolol. It is also effective The extent of IOP reduction and its duration is less
than latanoprost. Unoprostone has been shown to Its adverse effects and contraindications are
improve blood flow in the optic nerve head, retina the same as latanoprost.
and choroid by antagonizing the endothelin-1
induced vasospasm. It is, therefore, especially Ocular hypotensive lipids
useful in improving optic nerve circulation in
patients with vasospasm. Ocular hypotensive lipids are also PGF 2α
derivatives obtained by substituting carboxylic
acid moiety with neutral substitutes. They do not
Therapeutic Uses act on prostanoid receptors but at a concentration
Unoprostone isopropyl l0.12% is used twice a of 0.01%, reduce the IOP as effectively as
day in the treatment of ocular hypertension and latanoprost 0.001%. This novel groups of
POAG and is as efficacious as timolol 0.5% twice compounds has shown promising results.
a day. Unoprostone also reduces IOP significantly
in patients with normal tension glaucoma.
SYSTEMIC HYPEROSMOTIC AGENTS
Adverse Effects and Contraindications Systemically administered hyperosmotic agents
Prolonged use of unoprostone has not been are especially useful in the management of acute
shown to cause iris pigmentation as is the angle closure glaucoma and for IOP control
case with latanoprost. However, corneal before intraocular surgery. One of the examples
surface abnormalities have been reported. Like is glycerin. Oral form of glycerin creates osmotic
latanoprost, it has no systemic adverse effects. gradient between plasma and ocular fluids and
Contraindications for its use are also the same reduces IOP.
as for latanoprost. Additionally, it should be Ophthalmic use of 1 to 2 drops of glycerol
used carefully in patients with dry eyes and in reduces edema and removes the corneal haze by
combination of other topical drugs that are likely attracting water through semipermeable corneal
to cause corneal epithelial damage. epithelium so that the ophthalmoscopic and
goniosopic examination becomes easy in patients
with acute glaucoma. The detailed pharmacology
Travoprost
of hyperosmotic agents is described in Chapter
Travoprost is a newer PGF2α analog that pro 19 (A).
duces significant IOP lowering with once daily
instillation. It is most effective at 0.004%
concentration. It is used in ocular hypertension, RECENT ADVANCES IN
POAG and normal tension glaucoma. PHARMACOTHERAPY OF
Its adverse effects are generally mild and GLAUCOMA
contraindications are same as those for latanoprost.
Recent advances in glaucoma are directed towards
the better understanding of the pathways involved
Bimatoprost in retinal ganglion cell apoptosis, identification of
Bimatoprost 0.03% reduces IOP in patients therapeutic targets and, accordingly, development
with open-angle glaucoma. It should not be of therapeutic agents. Elevated IOP is only one of
administered more than once daily as the IOP the risk factors for glaucoma and the hallmark of
lowering effect may reduce when administered the disease, loss of retinal ganglion cells, is also
more frequently. Pressure starts reducing at about observed in patients with normal IOP. Despite
4 hours post-instillation and a maximum effect is this fact, current pharmacotherapeutic approaches
seen within 8 to 12 hours. primarily focus on lowering the IOP. Studies
are now being focused to explore the agents, cells.41 It could possibly be useful in neovascular
which along with reducing the IOP can provide glaucoma and may protect from gliosis.
neuroprotection. Brimonidine, an IOP-lowering agent has been
Use of neuroprotective drugs for the treatment reported to be a ganglion cell neuroprotectant.42
of certain neurodegenerative disorders of the CNS Muscarinic receptors may also be good therapeutic
such as Alzheimer’s and Parkinson’s disease targets for neuroprotection in glaucoma, as
led to the hypothesis of using neurotrophic has been demonstrated using galantamine that
(neuron survival) agents for the maintenance activates M1 and M4 muscarinic receptors.43 Alpha
of normal vision in glaucoma. 34,35 Loss of 2-macroglobulin has also been investigated as a
neurotrophin function in retinal ganglion cells target in ganglion cell neuroprotection.44
may be a contributing factor in the development Role of glutamate-mediated excitotoxicity
of glaucomatous optic neuropathy. Acute IOP in retinal ganglion cell apoptosis has been
elevation has previously been shown to obstruct investigated widely. Glutamate, a major excitatory
retrograde axonal transport in experimental neurotransmitter in the CNS and retina, is released
glaucoma.36 Receptors (TrkB) for brain derived by the presynaptic cells and acts on N-methyl-
neurotrophic factor (BDNF) have also been D-aspartate (NMDA), α-amino-3-hydroxy-5-
detected on retinal ganglion cells. In animal methyl-4-isoxazolepropionic acid (AMPA), and
models of glaucoma with acute elevation of IOP, kainite (KA) receptors.45 Excessive amounts of
retrograde transport of target-derived BDNF to glutamate results in excitotoxic neuronal death
the retina was found to be decreased. After BDNF mainly mediated through NMDA receptors in
administration increased survival of ganglion cell retinal ganglion cells. Vitreal glutamate levels
axons was observed.35,37-38 Studies have shown are increased in primary glaucoma. Fang et al.
that Lentiviral transduced BDNF-producing showed that bis(7)-tacrine had neuroprotective
mesenchymal stem cells can survive in eyes with effects against glutamate-induced RGCs damage
chronic hypertension and can provide retina and both in vitro and in vivo, possibly through the
optic nerve functional and structural protection. drug’s anti-NMDA receptor effects. Therefore, it
Therefore, transplantation of BDNF producing may potentially be useful for treating ischemic/
stem cells may be a viable treatment strategy for traumatic retinopathies inclusive of glaucoma.45
glaucoma.39 Ciliary neurotrophic factor (CNTF) High glutamate levels result in increased
injected into the eyes of rats with increased IOP inflow of Ca2+ in ganglion cells. Ca2+-dependent
has also been shown to reduce apoptosis. Clinical intracellular mechanisms that finally activate
trials are being undertaken using CNTF after caspases underlie the pathological progression of
observing its efficacy and safety in preclinical neurodegeneration in glaucoma. Calcium channel
studies.35 Efficacy of neurotrophic agents has also blockers have been investigated for preventing
been observed in photoreceptor degenerations and apoptotic neuronal loss in glaucoma and caspase
similar neuropathies. Their safety and efficacy inhibitor nipradilol has shown antiapototic effects
needs evaluation in preclinical glaucoma models. on retinal ganglion cells.46-47
Clinical trials using BDNF in glaucoma may Free radicals such as nitric oxide (NO) have
provide useful results. Drug delivery system also been shown to play a significant role in retinal
like encapsulated cell technology is available ganglion cell loss by disrupting mitochondrial
and effective and should be considered for use function, degrading DNA and causing apoptosis.
in glaucoma.35 Neufeld, et al. supported the theory that NO can
Another possible therapeutic agent in glaucoma cause neurotoxicity in the optic nerve head of
is pigment epithelium-derived factor (PEDF).40 patients with POAG.48 Experiments using NO-
Transfected PEDF is protective for ganglion inhibitors showed neuroprotection in animal
cells in mouse glaucoma model as it showed models.49 Levels of NO and endothelin-1 are
anti-inflammatory effects in preserving ganglion increased in the aqueous humor of POAG
patients and in patients with chronic closed- 4. Fernandez-Bahamonde JL, Alcaraz-Michelli
angle glaucoma.50 A new compound comprising V. The combined use of apraclonidine and
latanoprost and NO-donating moiety (NCX pilocarpine during laser iridotomy in a Hispanic
125, BOL-303259-X) was synthesized and it population. Ann Ophthalmol. 1990;22(12):446–9.
was found to successfully lower IOP in rabbit, 5. Croft MA, Oyen MJ, Gange SJ, et al. Aging
dog, and primate models of glaucoma. This effects on accommodation and outflow facility
compound is reportedly entering clinical trial.51 responses to pilocarpine in humans. Arch
Age-Related Eye Disease Study (AREDS) with Ophthalmol. 1996;114(5):586–92.
a selected subset of antioxidative agents showed 6. Chen HS, Steinmann WC, Spaeth GL. The
effects of chronic miotic therapy on the result of
that antioxidants have neuroprotective effects by
posterior chamber intraocular lens implantation
slowing down the disease progression. Several
and trabeculectomy in patients with glaucoma.
other antioxidant trials have been completed or
Ophthalmic Surg. 1989;20(11):784–8.
are in progress. It is probable that antioxidants
7. Van Buskirk EM. Hazards of medical glaucoma
would be effective in slowing down the ganglion therapy in the cataract patient. Ophthalmology.
cell death. 1982;89(3):238–41.
Activation and proliferation of glial cells 8. Weseley P, Leibmann J, Ritch R. Rhegmatogenous
possibly significantly contributes to glaucomatous retinal detachment after initiation of ocusert
ganglion cell death.52 Minocycline treatment has therapy. Am J Ophthalmol. 1991;112(4):458–9.
been shown to reduce retinal microglia activation 9. Zimmerman TJ. Pilocarpine. Ophthalmology.
and improvement in optic nerve integrity in 1981;88(1):85–8.
mouse model.53 10. Araujo SV, Bond JB, Wilson RP, M R Moster,
Several studies using herbal drugs have also C M Schmidt, Jr, and G L Spaeth. Long-term
shown promising results in lowering the elevated effects of apraclonidine. Br J Ophthalmol.
IOP in animal models. These plants were chosen on 1995;79(12):1098–101.
the basis of their antioxidant, anti-inflammatory, 11. Koskela T, Bribaker RF. Apraclonidine
antihypertensive, antiangiogenic activities. and timolol combined effects in previously
These herbal formulations have not shown any untreated normal subjects. Arch Ophthalmol.
side-effects in animal models of glaucoma and 1991;109(6):604–8.
may have potential as antiglaucoma agents.54-55 12. Toris CB, Tafoya ME, Camras CB, Yablonski
The clinical trials on herbal formulations are ME. Effect of apraclonidine on aqueous humor
warranted. dynamics in human eyes. Ophthalmology.
1995;102(3):456–61.
13. Yoles E, Muler S, Schwartz M. Injury-induced
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ChapteR 17
Drugs Used in Retinal Diseases
OVERVIEW Based on the severity of the disorder, DR

is classified into two types: Non-proliferative
Retinal diseases such as age-related macular (NPDR) and proliferative (PDR). 9 NPDR,
degeneration (AMD), retinal vein occlusion commonly known as background retinopathy, is
(RVO), retinal artery occlusion and diabetic an early stage of diabetic retinopathy. In this stage,
retinopathy (DR), as a cause of visual impairment blood or fluid leaks from tiny blood vessels within
and blindness are of major concern because the retina. Leaking fluid causes the retina to swell
the treatment of these conditions faces serious or to form deposits called exudates. NPDR may
challenges. AMD affects older individuals and be mild, moderate or severe.
can be nonexudative (dry) or exudative (wet). i. Mild NPDR: It is the initial phase of NPDR
The condition involves macula leading to loss and is characterized by the presence of at
of central visual fields. Central retinal artery and least one microaneurysm, and also dot, blot
vein occlusion lead to severe retinal damage due or flame-shaped hemorrhages. Hard exudates
to ischemia. Among all, DR is the most prevalent and cotton wool spots are usually not a feature
affecting vision of millions of people around the of mild NPDR.
world. ii. Moderate NPDR: It is the next and more
severe stage of NPDR. During this stage, some
DIABETIC RETINOPATHY of the small blood vessels in the retina may
become blocked. The blockade of these tiny
Diabetic Retinopathy (DR) is a disorder of micro blood vessels causes a decrease in the supply
vasculature of retina that occurs as a consequence of nutrients and oxygen to certain areas of the
of prolonged and uncontrolled hyperglycemic retina (Figs 17.1A and B).
state. It has been reported that more than 4% of iii. Severe NPDR: In severe NPDR significant
world population is diabetic and half of them number of small blood vessels in the retina
are suffering from DR at some stage of disease become blocked. As a result more areas
progression. DR affects all patients with Type-1 of retina are deprived of nourishment and
diabetes and more than 70% of Type 2 diabetic oxygen. Lack of sufficient oxygen supply
patients develop DR after 15 years of diabetes. to the retina results in retinal ischemia.
There are large number of studies conducted To overcome ischemic insult a variety of
in western world to set up database for the compensatory growth factor cascade are
epidemiology of DR. 1-8 However, there is a activated eventually causing raised retinal
paucity of data on DR in India and other Asian Vascular Endothelial Growth Factor (VEGF)
countries despite the fact that DR has become the and Protein Kinase-C-β (PKC-β) levels. These
leading cause of vision loss in all Asian countries. angiogenic growth factors are responsible for
A B
C D
E F
Figures 17.1A to F (A and B) Representative fundus photographs from patient with moderate NPDR showing
significant accumulation of hard exudates (arrow), microaneurysms and leakages at some areas (asterisk); (C)
Fundus photograph from patient with severe NPDR showing significantly high leakage at multiple areas (star)
and appearance of hard exudates; (D) Fundus photograph from patient with severe NPDR showing tortuous
blood vessels (arrow head), large deposits of hard exudates (arrow) and leakages in the fundus (star); (E) A
representative image from patient with PDR as evident from neovascularization of the optic disc (arrow), tortuous
vessel, appearance of hard exudates (arrow head) and retinal hemorrhage (star); (F) A fluorescein fundus
angiogram from a patient with PDR showing significant leakage of sodium fluorescein (star) and appearance of
microaneurysms in the form of hyperfluorescent dots (arrow heads)
Drugs Used in Retinal Diseases 231
the increased retinal vascular permeability and drugs have emerged as effective treatment
neovascularization (Figs17.1C and D). modalities in pathological choroidal and retinal
PDR is a more advanced form of DR and a neovascularization.10
major cause of vision loss in diabetic patients. It is Pegaptanib (Macugen ® ): Pegaptanib is an
characterized by neovascularization on optic disc aptamer, a pegylated modified oligonucleotide,
and in other areas of retina. Sometimes vessels which binds with extracellular VEGF 165 and
grow out of inner limiting membrane and bleed in prevents it from binding with the VEGF
the vitreous leading to significant vision loss (Figs receptors.11 Following intravitreal administration,
17.1E and F). it gets distributed into the retina, vitreous and
aqueous and is slowly absorbed in the systemic
Drugs Used in the Treatment of DR circulation. It is metabolized by nucleases and
is generally not affected by the cytochrome
Since the last two decades, there have been
P450 enzymes. Pegaptanib requires repeated
significant developments in the field of pharmaco
administration at 6 weeks intervals. At 0.3 mg
therapy of DR. For DR, the advent of laser
dose, no dose reduction is required in patients
photocoagulation three decades back, was really
with renal impairment.
useful in limiting vision loss in most of the cases
It is available as preservative-free, sterile,
and is still considered the gold standard. However,
aqueous solution in single dose pre-filled
corticosteroids and anti-VEGF agents have shown
syringes. The active ingredient is 0.3 mg of the
promising results with regards to the prevention
free acid form of the oligonucleotide without
of neovascularization, but remained limited in use
polyethylene glycol, in a volume of 90 µL. This
due to their short-lasting effects. More importantly
dose is equivalent to 1.6 mg of pegaptanib sodium
none of these agents have shown ability to substitute
(pegylated oligonucleotide) or 0.32 mg as the
the remarkable durability and effectiveness
sodium salt form of the oligonucleotide moiety.
of panretinal photocoagulation in preventing
The most frequently reported adverse events
vision loss in the late stages of DR. Therefore,
in patients treated with Macugen® 0.3 mg for up
pharmacotherapy of DR is still an adjunct to
to two years were anterior chamber inflammation,
panretinal photocoagulation (Table 17.1).
blurred vision, cataract, conjunctival hemorrhage,
corneal edema, eye discharge, eye irritation, eye
Anti-VEGF drugs pain, hypertension, increased intraocular pressure
VEGF is a secreted protein that stimulates the (IOP), ocular discomfort, punctate keratitis,
growth of vascular endothelial cells. It is known reduced visual acuity, visual disturbance, vitreous
to play a significant role in ocular pathologies floaters, and vitreous opacities.
associated with neovascularization and is, Macugen® is contraindicated in patients
therefore, a target for several pharmacological with ocular or periocular infections. It is
agents used to treat such conditions. also contraindicated in patients with known
VEGF exists in at least 4 isoforms consisting of hypersensitivity to pegaptanib sodium or any
121, 165, 189, and 206 amino acids. VEGF165 has other excipient in this product.
the greatest mitogenic activity and is the primary Ranibizumab (Lucentis®): It is also available for
mediator of pathologic neovascularization. intravitreal injection. It is a humanized monoclonal
The mitogenic, angiogenic and permeability antibody fragment against VEGF derived from
effects of VEGF are mediated through two parent murine antibody bevacizumab (Avastin®).
tyrosine kinase receptors VEGFR1 and VEGFR2. It is much smaller than parent molecule and
Binding of VEGF with its receptor stimulates binds more strongly with VEGF.12 It differs from
angiogenesis, induces inflammation and increases Macugen® in that it binds with all four isoforms
vascular permeability. Several anti-VEGF of VEGF.
Table 17.1 Summary of currently available drugs for diabetic retinopathy and associated retinal pathology
Drug/formulation Company Category/ Clinical phase Regulatory

mechanism approval
Triesence (40 Alcon Laboratories Anti-inflammatory - FDA-approved
mg/ml),IVTA* Inc.
Preservative-free
Injection
Trivaris (80 mg/ml), Allergan Inc. Anti-inflammatory - FDA-approved
IVTA* Preservative-
free Injection
I-vation, Intravitreal Surmodics Inc. Anti-inflammatory Phase I completed -
TA** Implant
lluvien, fluocinolone Alimera Sciences Anti-inflammatory Phase III completed Not FDA-approved
acetonide
Ozurdex, Allergan Inc. Anti-inflammatory Under Phase III FDA-approved for
Dexamethasone DME
IV*** implant
Avastin, Genentech Inc. Anti-VEGF Under Phase III Not FDA-approved
Bevacizumab
Lucentis, Genentech Inc. Anti-VEGF Under Phase III FDA-approved for
Ranibizumab AMD
Macugen, EyeTech Anti-VEGF - FDA-approved
Pegaptanib Pharmaceuticals
and Pfizer
VEGF Trap- Eye Regeneron and Anti-VEGF Phase II (DME)# Not FDA-approved
Bayer Healthcare Phase III (AMD and
Collaboration CRVO)
Vitrase, ISTA Vitreous clearing Undergoing Phase Not FDA-approved
hyaluronidase Pharmaceuticals agent III
*IVTA: Intravitreal triamcinolone acetonide;

**TA: Triamcinolone acetonide;
***IV: Intravitreal;
#
Diabetic macular edema.
Source: Kumar B, Gupta SK, Saxena R, Srivastava S. Current trends in the pharmacotherapy of diabetic retinopathy. J postgrad
med. 2012;58:132-9.
The drug has proven efficacy in wet AMD Ranibizumab is available for intravitreal
and macular edema caused by RVO. It is injection as preservative-free sterile, colorless to
administered intravitreally once a month. The pale yellow solution in single use vials containing
frequency of administration may be reduced to 0.5 mL of 10 mg/mL of lucentis.
once in 3 months after 4 months of treatment Besides the complications associated
but the efficacy reduces as compared to monthly with injection procedure other adverse
injections. Ranibizumab has also been used along effects include conjunctival hemorrhage, eye
with verteporfin photodynamic therapy in the pain, vitreous floaters, increased IOP, and
treatment of wet AMD.13 Verteporfin is a liposomal intraocular inflammation. Use of intravitreal
preparation containing photosensitizer verteporfin. anti-VEGF agents is also associated with arterial
After intravenous administration, liposomes thromboembolic events but the incidence is very
containing verteporfin accumulate in endothelial low. Like other proteins, anti-VEGF agents can
cells by endocytosis through LDL receptors.14 also produce immunoreactivity.
Lucentis ® is contraindicated in patients related macular edema due to recurrence of
with ocular or periocular infections. It is symptoms and adverse effects like elevated IOP
also contraindicated in patients with known and cataract. Another limitation for the use of this
hypersensitivity to lucentis or any other excipient steroid is that repeated injections (every 4 month)
in the product. are often required with standard 4 mg dose.
Bevacizumab (Avastin®): It is also a humanized For intravitreal administration, triamcinolone
monoclonal antibody, and was the first acetonide is available as preservative-free sterile
commercially available VEGF antibody. Like suspension at 40 and 80 mg/mL concentration.
ranibizumab, it also targets all isoforms of VEGF. Particle dispersion from suspension can
It is approved for use in many metastatic cancers initiate macrophage reaction causing sterile
such as colorectal, lung and breast. It prevents the endophthalmitis. Use of preparations with
hydrogel base limits the particle dispersion and
tumor growth by inhibiting proliferation of new
avoids sterile endophthalmitis.
capillaries. It is a low-cost alternative to lucentis.
Moreover, it has longer intravitreal half-life thus Dexamethasone is one of the most potent
reducing the frequency of administration.15,16 corticosteroid. It is used in the treatment of
It has also been used in the treatment of PDR, persistent macular edema associated with diabetic
neovascular glaucoma, diabetic macular edema, retinopathy, RVO and non-infectious uveitis.
retinopathy of prematurity and macular edema Intravitreal dexamethasone causes significant
secondary to RVO. Avastin® has no significant improvement in visual acuity, fluorescein leakage
effect when used with laser photocoagulation in and central retinal thickness in these patients.
patients of DR with significant macular edema. The half-life of dexamethasone after
However, it is effective in patients without intravitreal injection is short. A biodegradable
significant macular edema. dexamethasone intravitreal implant (Ozurdex/
Posurdex) is now available, which provides
Corticosteroids extended release of a total dose of 0.35 or 0.7
mg dexamethasone. It is a rod shaped implant
Steroids are potent anti-inflammatory agents. They consisting of dexamethasone dispersed in poly
inhibit the production of VEGF and breakdown of (lactic-co-glycolic) acid (PLGA) matrix. The
blood-retinal barrier. Owing to these properties implant is placed through pars plana incision
steroids have been the mainstay of treatment into the vitreous chamber outside the visual axis.
in several ocular diseases. For the treatment of It releases the active drug initially in high pulses
ophthalmic diseases steroids can be administered for a few weeks and then maintains sustained
by topical, systemic, retrobular or intraocular release for about 6 months.17-19 It is indicated for
route. Steroids that are used for intravitreal the treatment of macular edema following DR,
injection include triamcenolone acetonide, branch retinal vein occlusion or central retinal
dexamethasone and fluocinolone acetonide. vein occlusion.20 The adverse effects include
Dexamethasone and fluocinolone acetonide are
increased IOP, conjunctival hemorrhage, eye
also available as intravitreal implant.
pain, conjunctival congestion, cataract, vitreous
Triamcinolone acetonide modulates the detachment and headache.
epithelial cell resistance, reduces permeability Use of intravitreal dexamethasone is
of outer blood-retinal barrier, promotes exudate contraindicated in patients with active or suspected
reabsorption and down-regulates inflammatory ocular or periocular infections including most
stimuli. Triamcinolone acetonide has been viral diseases of the cornea and conjunctiva
increasingly used in the treatment of diabetic (epithelial herpes simplex keratitis, vaccinia,
macular edema, RVO and non-infectious uveitis. varicella), mycobacterial infections and fungal
Usefulness of triamcinolone is limited in uveitis diseases. It is also contraindicated in patients
with advanced glaucoma and patients with known mottling, hyperplasia, and atrophy. On the other
hypersensitivity to any of its components or to hand, wet or exudative AMD affects only 10%
other corticosteroids. of the patients but causes blindness among 90%
Fluocinolone acetonide, a non-biodegradable of them. It is characterized by the growth of
sustained release intravitreal implant consisting choroidal neovascular membranes.31 Neovascular
of 0.59 mg of fluocinolone acetonide (Retisert®), AMD results from repeated cycles of shedding,
is available for extended drug delivery.21-23 The degradation, and resynthesis of photoreceptor
implant consists of fluocinolone acetonide 1.5 mm outer segments, which induce metabolic stress
diameter pellet encased in a silicone elastomer cup within the outer retina and RPE. The resultant
with a release orifice.24,25 The device is implanted chronic ischemia and inflammation upregulates
in vitreous through a pars plana incision and after several inflammatory cytokines and growth
implantation, it releases active drug at a rate of factors such as VEGF, which promote the growth
0.3–0.4 µg/day for a period of 30 months. It is of choroidal neovascular membranes from
used in the treatment of macular edema associated the choriocapillaris into the sub-RPE space or
with DR, RVO and non-infectious uveitis. The subretinal space.32
implant is expensive and associated complications
include cataract and elevated IOP.
Current Pharmacotherapy of AMD
Vitreolytic Agent Laser Photocoagulation
Vitrase (hyaluronidase ovine, ISTA Pharm Thermal laser photocoagulation is a technique
aceuticals, Inc.) is the first and only pure, for treating a number of eye conditions including
preservative-free, thimerosal-free, ovine wet AMD. A thermal laser is directed into the
hyaluronidase, which is FDA-approved as a eye at abnormal blood vessels growing beneath
spreading agent. Intravitreal vitrase has shown the retina. The heat from the laser closes off
efficacy and safety in a Phase III clinical trial that the unwanted blood vessels, preventing further
investigated its ability to promote the clearance of leakage and vision loss. Apart from this,
vitreous hemorrhage in cases of PDR, although, thermal laser can also destroy surrounding
the agent is not FDA-approved for this purpose.26,27
retinal tissue resulting in scotomas. The use
of photocoagulation is effective for patients
AGE-RELATED MACULAR with lesions that are outside the center of the
DEGENERATION macula.33
Age-related macular degeneration (AMD) is Photodynamic Therapy

a major cause of global visual morbidity after
DR and is the leading cause of blindness among For photodynamic therapy, a light-sensitive dye,
people over 50 years of age.28 The prevalence of verteporfin (Visudyne), is injected intravenously.
AMD varies widely among different ethnic groups The dye accumulates in the neovascular tissue and
and genetic make-up is a predisposing factor in is activated upon exposure to non-thermal light at
the pathogenesis of AMD.29 It is estimated that by 689 nm. Free radicals generated due to activation
the year 2020, at least 80 million people will be cause cell death and subsequent occlusion of
affected by AMD globally.30 abnormal new vessels with little or no damage to
AMD is classified into Dry or Wet (neovas normal vessels. Although, photodynamic therapy
cular) AMD. Dry or nonexudative AMD affects is a FDA-approved method for the treatment of
90% of the patients and is characterized by AMD, it has not succeeded in preventing vision
drusen and retinal pigment epithelium (RPE) loss in AMD patients.34,35
Nutritional Agents Aflibercept is indicated for the treatment

of patients with wet AMD and macular edema
Lutein and zeaxanthin are the two major following CRVO. The recommended dose is 2 mg
carotenoids found in the human macula. 36-37 (0.05 mL) administered by intravitreal injection
These are structurally similar to β-carotene and every 4 weeks for the first 3 months, followed
are found in various colored fruits and green leafy by 2 mg (0.05 mL) via intravitreal injection
vegetables. Lutein and zeaxanthin have been once every 8 weeks. It is available as 40 mg/mL
reported to accumulate in the macular region of solution in a single-use vial. Use of aflibercept
the retina where their contents are up to 5 fold is contraindicated in patients with ocular or
higher than the peripheral retina.36 Zeaxanthin periocular infection and active intraocular
preferentially accumulates in the foveal region, inflammation.
whereas lutein is abundant in the perifoveal The most common adverse reactions (≥ 5%)
region.37,38 These pigments are collectively known reported in patients receiving aflibercept are
as the macular pigment. Definitive role of these conjunctival hemorrhage, eye pain, cataract,
pigments in AMD is not known, however, a recent
vitreous detachment, vitreous floaters and
systematic review and meta analysis involving
increased intraocular pressure. Recent clinical
6 longitudinal cohort studies has shown that
studies comparing the efficacy and safety of
dietary lutein and zeaxanthin is not significantly
aflibercept with ranibizumab over 2 years have
associated with a reduced risk of early AMD,
shown no appreciable difference in the vision gain
but an increase in their intake may be protective
and retinal thickness between patients treated with
against late AMD.39
aflibercept 2 mg every 4 weeks and ranibizumab.
Both drugs were well tolerated and incidence of
Anti-angiogenic Agents serious ocular events or systemic adverse effects
Antiangiogenic agents are of value in the was comparable between treatment groups.43,44
treatment of AMD as they inhibit VEGF-
mediated pathological changes in the retina.
Ranibizumab and bevacizumab have been RETINAL VEIN OCCLUSION
discussed in the previous section. Clinical trials
RVO is the second largest cause of visual
with ranibizumab and bevacizumab have shown
morbidity after DR. The prevalence of RVO has
that patients receiving protocol-driven treatment
been shown to vary from 0.7 to 1.6%.45,46 In a
have a 30–40% chance of achieving a 15-letter
(halving of the visual angle) improvement in population-based study, an overall incidence of
visual acuity.40-42 symptomatic RVO was found in 0.21% of patients
Aflibercept (EYLEA®) is a newer addition in aged 40 years or older.47 Hayreh et al. (1990)
this class of drugs. It was approved by FDA in investigated the demographic characteristics of
November 2011 for use in neovascular AMD. It various types of RVO in 1108 patients (1229
is a VEGF inhibitor administered as an intravitreal eyes).48 In this study, a male: female ratio of 1.2:1
injection. It is a fully human recombinant was noted. RVO is of two main types: Central
fusion protein that binds all isoforms of VEGF Retinal Vein Occlusion (CRVO) and Branch
and prevents their binding to VEGFR-1 and Retinal Vein Occlusion (BRVO).
VEGFR-2. Aflibercept also binds to placental BRVO may result from one or more of the
growth factor inhibiting its binding to VEGFR-1. following primary mechanisms:
Inhibition of the binding of VEGF to its receptors a. Compression of the vein at the arteriovenous
decreases inflammation and vascular permeability, (A/V) crossing: In majority of A/V crossings,
prevents the progression of neovascular AMD, the thin walled vein lies between the more
and prevents further loss of vision. rigid thick-walled artery and the highly cellular
retina. The sharing of the common adventitial A. Drugs for the Treatment of
sheath by artery and vein and narrowing of Obstructed Venous Blood Flow
the venous lumen that normally occurs at the
A/V crossing results in the pathogenesis of i. Antiplatelet and thrombolytic agents: Platelet
BRVO.49-52 aggregation has extensively been studied as
b. Degenerative changes in the vessel wall: It a causal factor for the pathogenesis of RVO.
has been suggested that trophic changes in Therefore, anti-platelet therapy improves
the venous endothelium and intima media , retinal microcirculation and is considered
due to compression by overlaying artery, may effective. Ticlopidine has shown better results
underlie the pathogenesis of BRVO.52,53-56 as compared to aspirin. Thrombolytic agents
c. Abnormal hematological factors: Several studies are used to lyse thrombus causing obstruction
have shown a relation between BRVO and to venous blood flow.59,60
hyperviscosity due to high hematocrit. Higher ii. Hemodiluants: Isovolemic hemodilution
blood viscosity causes poor blood flow and using hydroxyethyl starch or dextran has been
favors erythrocyte aggregation. Dysregulation investigated in several clinical trials but due to
of the thrombosis-fibrinolysis balance may also large variation in study protocols the evidence
be a contributory mechanism.52,57,58 supporting their use remains incomplete.61,62
The pathogenesis of CRVO is not completely iii. Troxerutin: Troxerutin inhibits erythrocyte
understood. The central retinal artery and vein aggregation, thus reduces blood viscosity and
share a common exit through optic nerve head increases the retinal microcirculation.63-79
and pass through a narrow opening in the lamina
cribrosa. Therefore, the vessels are in a tight B. Drugs for the Treatment of
compartment with limited space for displacement. Complications
Apart from anatomical susceptibility, a combina Drugs used for the treatment of complications
tion of several other factors including slowing associated with RVO include corticosteroids
of the blood flow, vessel wall changes and and anti-VEGF drugs. A detailed account of
rheological changes in the blood predispose to these drugs is presented under previous section
thrombus formation in the central retinal vein in on DR.
the region of the lamina cribrosa.
Although, there is no specific risk factor
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ChapteR 18
Drugs Used in the Treatment of Dry Eyes
OVERVIEW AQUEOUS ENHANCEMENT THERAPY

Dry eye or keratoconjunctivitis sicca is defined as The aqueous enhancement in dry eyes is achieved
“a disorder of the tear film due to tear deficiency or primarily by tear supplementation, although,
excessive tear evaporation that causes damage to methods can also be adapted for tear conservation.
the interpalpebral ocular surface and is associated The tear substitutes are most commonly used
with symptoms of discomfort” (National Eye for tear supplementation. Tear conservation
Institute, December 5–6, 1994). The discomfort can be achieved by reducing the evaporation or
may be intermittent or continuous with mild drainage of tears. Use of measures such as goggles
symptoms such as burning, itching or tearing and room humidifiers helps in reducing the
and blurring of vision. At times condition may be evaporation. Avoiding exposure to smoke, wind,
severe leading to keratitis, conjunctivitis, corneal heating, air-conditioning and fans also reduces
ulceration, scarring and permanent vision loss. tear evaporation. Non-medicated ointments
Depending upon the predominant cause of dry applied on the ocular surface can prevent tear
eye condition, it can be divided in two categories: evaporation. Obstruction of tear outflow pathways
aqueous deficiency and evaporative. Aqueous by surgical methods such as cautery, laser, punctal
deficient dry eye is the largest category and occurs plugs and tarsorrhaphy in severe cases helps to
due to reduced tear volume. Reduction in tear conserve tears on ocular surface.
volume may be due to dysfunctional lacrimal
gland or failure of lacrimal fluid transfer. The Tear Substitutes
evaporative dry eye occurs primarily either due
to dysfunction of meibomian glands or increased Tear substitutes are the mainstay of therapy
width of palpebral fissure. Both types of dry eye for mild to moderate aqueous tear deficiency
conditions can also occur simultaneously. Either and include artificial tear solutions, lubricant
of these conditions can result in abnormal tear ointments, lipid emulsions and autologous serum.
composition and properties. The goal of treatment
is to relieve symptoms, heal the ocular surface and Artificial Tear Solutions
prevent complications. Following approaches and
drug classes are commonly used in the treatment The artificial tear solutions are most commonly
of dry eye:1 used forms of tear substitutes. They are expected
1. Aqueous enhancement therapy to reproduce the physical, optical and metabolic
2. Anti-inflammatory therapy properties of natural tears as closely as possible.
3. Secretagogues Currently, there are no true therapeutic tear
4. Hormonal therapy replacements that also have biological activity.
5. Omega-3 fatty acids Their long residence time provides better tear
Drugs Used in the Treatment of Dry Eyes 241
film stability. Some additives in these solutions carboxymethylcellulose (CMC). They dissolve
may also be of value in treating the primary or in water producing solutions of varying viscosity.
secondary ocular damage. Most artificial tears Optical clarity and refractive index of these
are aqueous solutions and consist of: solutions is close to that of cornea. They are
1. Polymers to enhance viscosity, lubrication inert substances and are, therefore, non-toxic to
and retention time and include polyols, ocular tissue.
polysaccharides and vinyl derivatives. MC forms a viscous solution in water and
2. Electrolytes to maintain the osmolarity. is used in a concentration of 0.5–1%. At higher
3. Buffers to maintain appropriate pH. concentrations, the solutions are highly viscous
4. Preservative to kill or inhibit bacterial growth. and interfere with vision, make blinking difficult
5. Nutrients as supplements for conjunctival and and can damage the tear film and epithelium.
corneal metabolic requirements. MC is a highly stable compound at a wide range
6. Mucolytic agents to soften the mucus and of pH suitable for eye. During heat sterilization,
improve mucin quality it coagulates but re-dissolves on cooling. MC
Polymers: Polymers are added to artificial tears solutions do not support the growth of micro-
to enhance the viscosity, lubrication and retention organisms. Hydroxyethylcellulose and HPMC
time. Addition of polymers allows not only the form less viscous solutions as compared to MC
retention of added fluid for a longer time but also but consist of similar cohesive and emollient
increases corneal surface wettability, reduces properties as MC. CMC is an anionic polymer,
blink friction and surface tension. They may which has stronger bioadhesive properties than
get adsorbed to corneal surface and stabilize the HPMC. However, due to ionic charges, CMC
thicker layer of fluid adjacent to adsorbed surface. may form insoluble complexes with tear film
They prolong the tear break up time (TBUT). components. Neutral polymers like HPMC or
The polymers commonly used in artificial tears MC are highly water soluble and do not form
include polyols, polysaccharides and vinyl such complexes.
derivatives. In addition to their therapeutic use in dry eye
Polyols that are commonly used include glycerin, conditions, substituted cellulose ethers are also
polyethylene glycol, propylene glycol and used to moisten the contact lenses. They are also
polysorbate 80. They have high water binding added to ophthalmic drug solutions to increase
properties. They lubricate the ocular surface the retention time of active drug on the ocular
and relieve the symptoms of dry eye. Glycerin surface. Their highly viscous solutions, such as
is used in 0.2–1% concentration. Polyethylene HPMC 2.5%, are used to apply gonioscopic lens
glycol is used in a concentration of 0.25–1%, to the eye. This helps to prevent damage to corneal
propylene glycol 0.3–1% and polysorbate 80 in epithelium.
a concentration of 1%. HP guar is a non-cellulose polysaccharide.
Polysaccharide polymers used in artificial tears It is derived from guar gum. It is used as a
include mucilages (substituted cellulose ethers), gelling agent along with borate and sorbitol. In
hydroxypropyl guar (HP guar), dextran and the formulation, sorbitol competes with borate
viscoelastic agents. Although, dextran (0.1%), and reduces cross-linking of HP guar. However,
a branched chain glucose polymer, is used when applied to ocular surface, sorbitol diffuses
frequently; use of substituted cellulose ethers, away due to its high water solubility. This allows
HP guar and viscoelastic agents is more common. borate to promote cross linking of HP guar in the
Substituted cellulose ethers used in presence of divalent cations normally present
artificial tears include methylcellulose (MC), in the tear film. The gelling of HP guar on the
hydroxyethylcellulose, hydroxypropyl cellulose, ocular surface helps in stabilizing the tear film
hydroxypropyl methylcellulose (HPMC) and and reducing the dry eye symptoms.
Viscoelastic agents include sodium hyaluro- avoided. PVA is commonly used in a concentration
nate and chondroitin sulfate. They are muco- of 1.4%. At this concentration although less viscous
polysaccharides and are normally present in the than MC, it significantly increases the corneal
extracellular matrix of connective tissue including residence time. It enhances the tear film stability
that of ocular tissue. Although primarily used and increases TBUT. It is also used as wetting
during intraocular surgery, they are also used in agent in contact lens solutions. It is non-irritant to
the treatment of severe dry eye conditions due to eye and does not interfere with conjunctival and
their lubricating properties. corneal epithelial integrity. PVP is a non-ionic
Sodium hyaluronate, a hydrophilic, high surfactant and is used in a concentration of 3–5%.
molecular weight compound, is 500,000 times more It increases the viscosity of solutions. Its ability to
viscous than normal saline. It lubricates as well as reduce surface tension at oil-water interface is less
protects the ocular surface. Various investigators than that of cellulose ethers. However, it improves
have described its use in concentrations ranging the wetting ability of corneal surface by forming a
from 0.1 to 0.5%. In severe dry eye conditions, hydrophilic coating in the form of adsorbed layer
topical application provides quick relief of resembling the coating formed by conjunctival
symptoms. Rose bengal staining of cornea and mucin. It is, therefore, useful in mucin and aqueous
conjunctiva decreases, corneal luster increases deficient dry eyes.
and TBUT increases significantly. The effects of
Electrolytes: Electrolytes such as salts of sodium
sodium hyaluronate in increasing the thickness
and potassium are added to artificial tear solutions
of corneal tear film are better than the aqueous
to maintain osmolarity. Most of the solutions are
artificial tears. Topical application of sodium
isotonic with natural tears. Hypertonicity in tear
hyaluronate has also been shown to reduce
film causes cell shrinkage due to loss of water,
fluorescein staining thus indicating improved cell-
reduces cell viability and disrupts mucin layer.
to-cell adhesions in cornea. Sodium hyaluronate is
Sometimes, hypotonic solutions are used in dry
a non-toxic substance. It is available in disposable
eye patients to allow the tonicity of tears to drop
syringes. Its use in dry eye conditions is limited
to the levels seen in non-dry eyes. Electrolytes are
due to high cost.
also added to artificial tear solutions to provide
Chondroitin sulfate is 350,000 times more
nutrition for corneal epithelial metabolism and as
viscous than saline. Frequent topical instillation
a part of buffer system.
in a concentration of 1% can effectively relieve
the symptoms of dry eye. It is available as a Buffers: The natural tear film components such
mixture of sodium chonrdroitin sulfate, 40 mg/ as bicarbonates, proteins, phosphates and others
mL and sodium hyaluronate 30 mg/mL in 0.5 mL maintain a pH of 7.4. Artificial tears for dry eyes
disposable syringe. have alkaline pH (~8.5) and are most comfortable
Vinyl derivatives like polyvinyl alcohol (PVA), at this pH. Commonly used buffer systems include
polyvinylpyrrolidone (PVP), polyvinyl acid and phosphate, phosphate-acetate, phosphate-citrate,
polyvinyl chloride are water soluble polymers. phosphate-citrate-bicarboante, borate and sodium
PVA in solution is clear and transparent with hydroxide.
refractive index approximately equal to distilled Preservatives: Preservatives are added to arti
water. It is highly stable even at high temperature ficial tears to kill or inhibit the growth of
and, therefore, can be sterilized by autoclaving. microorganisms. Contaminated solutions are
It is compatible with most of the commonly used likely to cause infection in dry eyes. Commonly
drugs and preservatives except sodium borate, used preservatives include: quaternary ammonium
bicarbonate and sulfate, potassium and zinc sulfate. compounds (BAK and polyquad), mercurials
Concomitant use of solutions containing these (thimerosal), alcohols (chlorobutanol) and esters
electrolytes and those containing PVA should be of parahydroxybenzoic acid (methyl and propyl
paraben). EDTA is added to enhance the activity Lubricant Ointments
of quaternary ammonium compounds. Use of
preserved tears is associated with epithelial Lubricant ointments have a longer contact time
toxicity, tear film instability and hypersensitivity and coat the ocular surface well during sleep when
aqueous tear production is normally reduced.
especially when used multiple times a day for
They typically contain oily substances such
prolonged period. Moreover, preservatives
as lanolin and petrolatum, which prevent tear
bind with contact lens polymer and prolong the
evaporation. Preservative free ointments are now
residence time on corneal surface. Therefore,
available. Daytime application causes blurred
use of preserved tears with contact lenses
vision and sticky sensation. Non-blurring gels
further enhances the possibility of toxicity and
that dissipate rapidly are available for effective
hypersensitivity reactions. Patients requiring
use during the day in severe dry eye.2
daily instillations of more than 3–4 times, are
recommended to use unpreserved solutions,
which are available as single-dose packages. Their
Lipid Emulsion
use is inconvenient and expensive and requires Lipid emulsions are available for long-lasting
additional precautions to prevent contamination lubrication by fortifying the lipid component
and infection. Newer preservatives used in of the tear film. Lipid emulsions consist of
ophthalmic formulations break down on exposure oils like castor oil or mineral oil, viscosity
to ocular surface or light. Sodium perborate enhancer like carbomer, lubricants like glycerin,
preserves the solution by generating very low polysorbate and preservative. These agents
quantities of hydrogen peroxide. When applied provide temporary symptomatic relief but do
to ocular surface, it breaks down to hydrogen not reverse the ocular surface pathology. They
peroxide, which further degrades to water and have no direct anti-inflammatory effect although
oxygen. Sodium chlorate used as preservative decrease inflammation indirectly by reducing
degrades to sodium chloride and water upon tear osmolarity and diluting the concentration of
exposure to light. inflammatory factors on the ocular surface.
Nutrients: Nutrients are added to support con Autologous Serum

junctival and corneal metabolism. Water is most
important component besides dextrose, sodium Autologous serum contains growth factors such as
lactate, sodium citrate, vitamins A and B12. fibronectin, vitamin A, epidermal growth factors
and TGF-β that are normally present in the natural
Mucolytic Agents: Mucolytic agents include tears. It may provide anti-inflammatory effect by
bromhexine, acetylcysteine, tyloxapol, and inhibiting the inflammatory cascades on the ocular
methylcysteine. These agents soften the mucus surface. A major limitation of this therapy is that it
and decrease the tear film viscosity. They requires special preparation and carries the risk of
stimulate the goblet cells for mucus production. infection. It is useful for most severe cases of dry eye
The sodium salt of acetylcysteine is available as that have conjunctival metaplasia as seen in Stevens-
10 or 20% solution for use in acute or chronic Johnson syndrome and Sjogren’s syndrome.3
bronchopulmonary conditions. This solution is
diluted with saline or artificial tears to 2–3%
concentration for topical ocular use. The solution ANTI-INFLAMMATORY THERAPY
helps to dissolve the mucus threads but as it
causes stinging sensation upon application,
Cyclosporin A
subjective improvement of dry eye symptoms is Cyclosporin A (CsA) is useful in the management
not significant. of moderate to severe dry eye disease. It is a
fungal-derived peptide that prevents the activation Systemic doxycycline has been reported to
of transcription factors that are necessary for improve irritation symptoms, increase tear film
T-cell activation and the production of interleukin stability and decrease the severity of ocular surface
2. The phase 2 FDA clinical trial evaluated four disease. It is recommended for patients with dry
doses of CsA (0.05%, 0.1%, 0.2%, 0.4%). The eyes with significant component of meibomian
0.1% concentration was found to improve the gland disease. Main side-effects are increased skin
objective end-points most consistently while the photosensitivity and gastrointestinal complaints.
0.05% concentration gave the most consistent The latter side-effects diminish with lower doses.
improvement in subjective symptoms. phase 3
clinical trials showed that the patients treated
with CsA 0.1% or 0.05% had significantly SECRETAGOGUES
greater improvement in two objective signs of
Secretagogues are therapeutic agents that stimulate
dry eye disease, corneal fluorescein staining
tear secretion. Systemic cholinergic agents such
and anesthetized Schirmer test values. Both
as pilocarpine (Salagen TM) have successfully
doses of CsA gave an excellent safety profile
been used to treat dry eyes in Sjogren’s syndrome
with no significant systemic or ocular adverse
patients. Cevimeline (EvoxacTM) a cholinergic
events except for transient burning symptoms
agonist with high affinity to the muscarinic M1 and
after instillation. The clinical improvement has
M3 receptors and long-lasting sialogenic effect has
been accompanied by decreased expression of
a better side effect profile.
activation markers (HLA-DR), apoptosis markers,
The main limitation of these agents are
inflammatory cytokines and infiltrating T cells.
their systemic cholinergic side-effects such
The density of goblet cells increased on the ocular
as nausea, sweating and abdominal cramps.
surface. No CsA was detected in the blood of
Although they are officially approved for mouth
patients treated with topical CsA for 12 months.
symptoms only, they may improve ocular
symptoms in those with residual lacrimal gland
Corticosteroids function. Besides, cholinergic agents, topical
Corticosteroids act by non-specifically inhibiting UTP and other nucleotides have been shown
many aspects of the inflammatory response. Several to stimulate the P2Y2 purinergic receptors to
clinical studies have demonstrated their efficacy induce secretion of mucin, chloride and fluid by
in improving the signs and symptoms of dry eyes. conjunctival cells.
In patients with significant inflammatory disease
such as Sjogren’s syndrome, topical steroids may
not be adequate and a short pulse of systemic HORMONAL THERAPY
corticosteroids can be more effective. Overall,
Androgenic steroids may have beneficial effect
topical steroids are effective for achieving a quick
for the ocular manifestations of Sjogren’s
response. Due to many ocular complications of
syndrome based on laboratory and epidemiologic
topical steroids, recommendation is to limit its use
studies that suggest the low incidence of the
as pulse therapy to control exacerbations followed
disease in males. Androgenic hormones such
by substitution with low potency agents.
as testosterone appear to attenuate autoimmune
reactions while estrogens have been implicated
Tetracycline in the pathogenesis and progression of many
Tetracycline is a class of antibiotic that has anti- autoimmune disorders. Systemic androgen has
inflammatory properties, which include reduced immunosuppressive effects on the lacrimal
cytokines, nitric oxide and expression of HLA class gland. It has been reported that women with
II and inhibition of matrix metalloproteinases. primary and secondary Sjogren’s syndrome are
androgen deficient. Moreover, estrogens appear surface. However, new insights into the inflam
to contribute to the development of dry eyes. matory nature of this disease have shifted
Hormone replacement therapy in postmenopausal the therapeutic approach to dry eyes towards
women is associated with a significant increase in suppressing the inflammatory response on the
the prevalence of dry eye symptoms. The effects ocular surface. Tear substitutes continue to be
of sex steroids on the tear function are mediated the first line of treatment and anti-inflammatory
through both meibomian and lacrimal glands. therapy may be considered for patients with
Treatment with testosterone undecanoate has ocular surface disease or for those who continue
been shown to provide significant improvement in to be symptomatic despite copious lubrication.
Schirmer test values and ocular surface staining.
REFERENCES
OMEGA-3 FATTY ACIDS
1. Djalilian AR, Hamarh P, Pflugfleder SC. Dry
Tears contain essential fatty acids omega-3 and eye. In: Krachmer JH, Mannis MJ, Holland EJ,
omega-6, which are only obtained through diet. (eds). Cornea. 2nd edn. Elsevier Mosby. 2005.
Essential fatty acids are found in various foods pp. 521–42.
such as flaxseed, blackcurrant seed, canola oil, 2. Davitt WF, Blooenstein M, Martin A, Christensen
MT, Martin AE. Efficacy in patients with dry
walnuts, soy and cold-water fish, e.g. mackerel,
eye after treatment with a new lubricant eye
tuna, salmon, sardines and herring. A higher ratio drop formulation. J Ocul Pharmacol Ther.
of omega-6 to omega-3 fatty acid supplement 2010;26(4):347–53.
consumption may decrease incidence of dry eye 3. Pensyl CD. Preparation for Dry Eye and Ocular
syndrome. Surface Disease. In: Bartlett JD, Jaanus SD, (eds).
The treatment of dry eyes has traditionally Clinical Ocular Pharmacology, 4th ed. Boston:
involved hydrating and lubricating the ocular Butterworth-Heinemann. 2001; pp. 315–31.
ChapteR 19
Miscellaneous Drugs
A. Hyperosmotic Agents
Vinay Gupta, Preeti Sankaran, Sujaya Singh, Sushil Vasudevan
OVERVIEW SYSTEMIC HYPEROSMOTIC AGENTS

Hyperosmotic agents are the drugs used in Pharmacology of systemic
the management of acute glaucomas and
occasionally for reduction of corneal edema. For
hyperosmotic agents
the glaucomas, they are administered either orally
Mechanism of Action,
or intravenously to increase the osmotic pressure
of plasma in relation to that of ocular tissues. Pharmacodynamics and
Fluid from the ocular tissues hence moves into Pharmacokinetics
the plasma as a result of the osmotic gradient Systemic hyperosmotic agents lower the
produced. They are used when rapid reduction
intraocular pressure through two mechanisms.1
of intraocular pressure is needed before definitive
Firstly they cause reduction in the volume of
treatment is carried out and prior to intraocular
surgeries. However, they have potentially fatal vitreous humour through relative increase in the
adverse effects and thus are not suitable for long- osmolality of the intravascular fluid. These agents
term therapy of glaucoma. penetrate slowly in the vitreous, which results in
For corneal edema they are administered the creation of an osmotic gradient that draws
topically to increase the osmotic pressure of fluid out of the vitreous into the intravascular
the tears. The osmotic gradient thus created space. Hence, reduction in the total vitreous
allows fluid from the cornea to move into the volume causes reduction of intraocular pressure.
hyperosmolar tear film (Table 19.1). Secondly, they also have a secondary effect on the
Table 19.1 Classification of hyperosmotic agents
Systemic agents Topical agents

Intravenous hyperosmotic agents Oral hyperosmotic agents
1. Mannitol 1. Glycerol 1. Hypertonic sodium chloride

2. Urea (not in use) 2. Isosorbide (not in use) 2. Glycerol
Miscellaneous Drugs 247
osmoreceptors in the hypothalamic center of the 6. Rate of excretion: Drugs which are cleared
central nervous system. However, this secondary from the circulation rapidly have less effect
mechanism does not play a significant role in the on blood osmolality and intraocular pressure.
reduction of intraocular pressue. Mannitol and Topical hyperosmotic agents are mainly
glycerol penetrate the blood ocular barrier poorly, used to decrease corneal edema by creating an
which is of advantage as it creates a larger osmotic osmotic gradient between the edematous cornea
gradient for water to follow. and the tear film, thereby, drawing fluid from
The decrease in intraocular pressure with hy- the edematous cornea to the hyperosmolar tear
perosmotic agents depends on the osmotic gradient film, which is then eliminated through the usual
created, which in turn depends on the following: lacrimal drainage system (Table 19.2).
1. Molecular weight: Lower the molecular weight,
greater the number of milliosmoles per dose Therapeutic Uses
and greater the efficacy. For example, urea
(molecular weight = 60) has more mOsm per Systemic hyperosmotic agents are indicated in acute
gram than mannitol (molecular weight = 182). glaucomas (e.g. acute angle-closure, malignant
2. Dose given and weight of the patient. glaucoma, post-traumatic glaucoma) for short-term
3. Rate and route of administration: More rapid and for rapid reduction of intraocular pressure prior
and greater effect is achieved with intravenous to definitive medical or surgical management.
administration than by the oral route. They may also be used prior to intraocular surgery,
4. Distribution in fluid compartments: Drugs like cataract surgery, penetrating keratoplasty,
which are confined to the extracellular trabeculectomy, non-draining sclera buckling.
compartment (e.g. mannitol, glycerol) increase Glycerol is of significant value in the management
the osmotic gradient to a greater extent than of acute angle-closure glaucoma as it not only
drugs distributed in total body water (e.g. urea, reduces the intraocular pressure but may also
isosorbide) at the same dose in milliosmoles. cause a readjustment in the intraocular volume and
5. Ocular penetration: Drugs with poor ocular pressure in the posterior and anterior chamber in
such a way that the angle closure is corrected and
penetration (e.g. mannitol, glycerol) achieve
normal aqueous humor dynamics is re-established.
a greater osmotic gradient than those which
Topical hyperosmotic agents are indicated
enter the eye rapidly (e.g. urea, isosorbide).
for reducing corneal edema due to various
Hyperosmotics which enter the eye, however,
causes like bullous keratopathy, acute angle
still enter the vitreous slowly. A blood-vitreous
closure glaucoma, corneal hydrops, and Fuch’s
gradient is, therefore, created. As water leaves
endothelial dystrophy.
the eye, osmolality of the vitreous increases.
However, as the drug gets cleared from the
blood, the gradient may get reversed and
Adverse Effects
may cause rebound increase in intraocular The adverse effects of systemic hyperosmotic
pressure.2 agents include:1,3,4
Table 19.2 Pharmacokinetics of systemic hyperosmotics
Distribution in body compartments Ocular penetration Metabolism Excretion

Mannitol Extracellular Poor Not metabolized Renal
Urea Total body water Good Not metabolized Renal
Glycerol Extracellular Poor Metabolized Renal
Isosorbide Total body water Good Not metabolized Renal
1. Nausea and vomiting occur often with cardiac arrhythmia or hyperosmolar non-ketotic
oral agents especially with glycerol. This coma leading to death have been reported.
may cause difficulties when administered
preoperatively. Nausea may be avoided by Contraindications
administering glycerol with a flavored vehicle.
2. Diuresis, urinary retention Use of glycerol is contraindicated in patients
3. Dehydration with anuria, frank pulmonary edema or those
4. Acidemia with severe cardiac decompensation. Diabetes is
5. Anaphylactic shock a relative contraindication for the use of glycerol.
6. Cardiovascular overload
7. Pulmonary edema Precautions
8. Anuria Caution should be exercised in patients with
9. Backache, headache, disorientation hypovolemia, confused mental states, congestive
10. Fever, chills. heart failure and dehydration such as in diabetics.
The adverse effects of topical hyperosmotic Safety and effectiveness in children have not
agents are mainly temporary burning, irritation
been established. Caution should be exercised
and blurring of vision on instillation.
while administering it before ocular surgery as it
may induce nausea and vomiting. Caution is also
Contraindications required in the elderly senile patients especially
Systemic hyperosmotic agents are contraindicated with history of urinary retention, diabetes, cardiac
in patients with compromised cardiac function as problems and severe dehydration.
they may cause circulatory overload and are to
be used with caution in renal disease. Glycerol is Dosage and administration
relatively contraindicated in diabetic patients as it
Glycerol is administered orally at a dose of 1–1.5
increases the risk of hyperglycemia and ketosis.5
g/kg body weight (2–3 mL of 50% glycerol/kg
Topical hyperosmotic agents are contraindi
body weight/dose). Peak effect occurs 1 to 1.5
cated in patients with hypersensitivity to its
contents. hours after administration and lasts for 5 hours.
Glycerol needs to be administered in a flavored
vehicle such as with lemon juice or over ice to
Glycerol (Glycerin)
avoid severe nausea due to its unpleasantly sweet
The chemical name of glycerin is 1, 2, taste.6 In elderly patients, the minimum dose
3-Propanetriol. Glycerin 50% and 75% is an oral (1 g/kg) required to produce the desired effect
osmotic agent for reducing intraocular pressure. should be used to avoid side-effects.
Indications and Usage Mannitol

Glycerin 50% or 75% is indicated in the treatment Mannitol is currently the most commonly used
of glaucoma to interrupt acute attacks and in cases intravenous hyperosmotic agent. It is more
where a temporary drop in pressure is required useful than urea as an intravenously administered
which cannot be readily obtained by other means. osmotic agent for reducing intraocular pressure.
Adverse Effects Mechanism of Action

Nausea, vomiting, headache, confusion and The mannitol molecule is three times larger than
disorientation may occur. Severe dehydration, that of urea, but it exerts a comparable osmotic
effect. This is because it is concentrated in the Mannitol 20% solution is given intravenously
extracellular fluid compartments, which contain at a dose of 1–2 g/kg over a 30 minute period
only one third of the total body water. As with (7–10 mL/kg). The duration of administration
urea, the mannitol induced pressure lowering may vary from 20 to 45 minutes, but it should be
effect coincides with the increase in serum given slowly as rapid infusion causes a shift of
osmotic pressure. This ocular hypotensive effect intracellular water into the extracellular space,
occurs in 30–60 minutes, depending on the rate causing cellular dehydration with a high risk of
of infusion, and lasts for about 6 hours. Because hyponatremia, congestive cardiac failure) and
of vitreous dehydration, the anterior chamber pulmonary edema. Peak intraocular pressure
deepens with intravenous infusion of mannitol reduction occurs 1–1.5 hours after administration
as with urea. and lasts for 2–6 hours.
Indications and Usage

Isosorbide
Same as for glycerol.
The chemical name of isosorbide is 1, 4:3,
Adverse Effects 6-dianhydro-D-glucitol. Isosorbide 45% w/v
oral solution is a dihydric alcohol prepared in a
All osmotic agents may produce headache, flavored vehicle.
dizziness and backache, presumably from cerebral Isosorbide is readily absorbed after oral
dehydration and decreased cerebrospinal fluid administration. It is not metabolized and remains
volume. Dryness of mouth and increased thirst in circulation until eliminated by kidneys
often occur. Fluid and electrolyte imbalance and unchanged. The physical action of isosorbide is
acidosis may occur. Movement of potassium from
similar to that of other osmotic agents.
intracellular to extracellular fluid may induce
hyperkalemia.
Contraindications Isosorbide is used for the short-term reduction of
Same as for glycerol intraocular pressure to interrupt an acute attack
of glaucoma. It may be used prior to and after
Precautions intraocular surgery. It is used when there is less
risk of nausea and vomiting than that posed by
Patients with impaired cardiovascular status
other oral hyperosmotic agents is needed.
may suddenly decompensate with congestive
heart failure. By diuresis, mannitol may
intensify inadequate hydration or hypovolemia. Adverse Effects
Measurements of serum electrolytes such as
sodium and potassium are, therefore, important Nausea, vomiting, headache, confusion and
in monitoring patients on combination of oral disorientation may occur. Very rare occurrences
acetazolamide, glycerol and mannitol. of syncope, gastric discomfort, lethargy, vertigo,
thirst, dizziness, hiccups, irritability, rash and light
headedness have been reported.
Dosage and Administration
Mannitol solution tends to crystallize at cooler Contraindications
temperatures. The crystals will go back into
solution if the container is warmed, hence bottle Same as for glycerol. However, it is relatively
should be shaken well before use. safer in diabetics than glycerol.
Precautions Contraindications
With repeated doses, consideration should be Use of topical glycerol is contraindicated in pa-
given to maintenance of adequate fluid and tients with hypersensitivity to the active ingredi-
electrolyte balance. If urinary output continues ents or preservatives used in formulation.
to decrease, the patient’s clinical status should
be closely reviewed. Accumulation of isosorbide Precaution
may result in over-expansion of the extracellular
fluid. Glycerol is an irritant and hence, instillation of
Repetitive doses should be used with caution topical anesthetic prior to instillation of glycerol
particularly in patients with diseases associated is useful.
with salt retention. It is important to ensure
that patient’s bladder has been emptied prior to Dosage and Administration
surgery. One or two drops of topical glycerol are
administered prior to ophthalmic or gonioscopic
Dosage and administration examination.7
The recommended initial dose is 1.5 g/kg body
weight of isosorbide 45%. The onset of action is Topical Hypertonic Saline
usually within 30 minutes while the maximum Topical hypertonic saline (sodium chloride) is
effect is expected at 1 to 1.5 hours and lasts for used as sodium chloride 2, 3 and 5% ophthalmic
3–5 hours. eye drops or sodium chloride 5% ophthalmic
ointment.
Topical Hyperosmotic Agents
Topical Glycerol (Glycerin) It is usually used for the temporary relief of
The chemical name of glycerol is 1, 2, 3-Propa- corneal edema caused by bullous keratopathy,
netriol. Topical glycerol is usually available as a Fuch’s endothelial dystrophy and acute
clear, colorless viscous solution. hydrops.
Indications and usage Adverse Effects

Topical glycerol is usually used to temporarily It may cause temporary irritation and burning on
clear an edematous cornea to facilitate ophthalm instillation of the eye drops.
oscopic and gonioscopic examination of the eye
in conditions like acute angle-closure glaucoma, Contraindications
bullous keratopathy, Fuch’s endothelial
dystrophy and corneal hydrops. Its action Its use is contraindicated in patients with
is transient and hence is used for diagnostic hypersensitivity to the active ingredient or
purposes only. preservatives used in formulation.
Adverse Effects Dosage and Administration

It may cause pain and irritation on instillation of 1 or 2 drops in the affected eye(s) every 3–4
the drops. hours.7
Summary hyperosmotic agents administered by intravenous

and oral routes respectively. Their use may be
Systemic hyperosmotic agents are used in associated with serious systemic adverse effects,
emergency situations where rapid reduction therefore, they should be used with caution.
of intraocular pressure is required. Mannitol Topical hyperosmotic agents are generally
and glycerol are the most commonly used used for temporary relief of corneal edema.
B. Surgical Adjuncts
Puneet Agarwal
OVERVIEW and depends on aqueous humor for its glucose and

oxygen supply.10 However, during short periods
A variety of agents are used as adjuncts in various of interruption in nutrient supply, lens maintains
ophthalmological procedures and surgeries. In its energy supply by anaerobic metabolism and is
intraocular surgeries such adjuncts are the vital not dependent on nutrients in intraocular irrigation
components. Commonly used surgical adjuncts fluids.11 Prolonged deprivation of glucose can,
in ophthalmic procedures include irrigating however, cause cataract development. Retinal
solutions, viscoelastic agents, enzymes, chelating tissue obtains nourishment from ocular vessels.
agents, caustics and adhesives. As stated above, the corneal endothelial cells
obtain glucose and oxygen largely from aqueous
humor. The cells in corneal endothelium contain
INTRAOCULAR IRRIGATING large number of mitochondria and depend to
SOLUTIONS a great extent on aerobic metabolism. 12 The
endothelium is the most important component of
Intraocular irrigating solutions serve as perfusion cornea in maintaining its hydration and clarity.13,14
medium during surgery. They clean the tissue and Therefore, during intraocular surgery corneal
maintain its hydration. Most importantly, they
endothelial cells must be supplied with glucose in
are composed in a way to meet the metabolic
irrigating solution as they are the most vulnerable
requirement of ocular tissue for the period of
to interruption in nutrient supply.
disruption of nutrient supply during surgical
To maintain the cell viability during surgical
procedure.
procedure, irrigation solutions are formulated to
The corneal epithelial cells derive energy to
match the physiological conditions. Accordingly,
a great extent by anaerobic metabolism. They
receive glucose supply primarily from aqueous the pH of intraocular irrigation solutions is
humor and some from limbal vessels.8 They also adjusted at approximately 7.4 and the osmolality
store glucose as glycogen. During short periods at approximately 300 mOsm. A variation in
of interruption in nutrient supply as occurs pH or the osmolality is likely to damage the
during intraocular surgery, corneal epithelial structure and function of the ocular tissue. The
cells can rely on their own glycogen stores. The intraocular irrigating solutions also contain
keratocytes in stroma derive energy from both the sodium, potassium, magnesium, calcium, chloride
aerobic and anaerobic metabolism. Their glucose and bicarbonate.15,16 These ions are required to
supply is from aqueous humor. Their dependence maintain cell adhesions and cell-to-cell junctions.
on glucose contents of intraocular irrigating Due to their toxic effects on ocular tissue and
solutions is not well established. The corneal doubtful efficacy against intraocular infections,
endothelium obtains its nutrient supply from preservatives are not used in intraocular
aqueous humor and derives energy by aerobic irrigation solutions. Intraocular toxicities due
metabolism. The cells in conjunctiva and uvea to preservatives include damage to corneal
receive their oxygen and glucose supply through endothelial cells, iritis and lens opacification. The
rich network of conjunctival and uveal vessels three types of intraocular irrigating solutions in
respectively.9 Lens has a very low metabolic rate use include:
1. Balanced salt solution (BSS) if the intraocular surgery is to be done without
2. Lactated Ringer’s solution the use of a viscoelastic agent, a complete
3. Balanced salt solution plus (complete) irrigation solution is required to adequately
BSS consists of chlorides of sodium, potassium, protect corneal endothelium even if the surgery
calcium and magnesium, sodium acetate and lasts for less than 1 hour.24 Diabetic patients have
sodium citrate. It is acceptable for short-term high polyol contents in lens fibers, which exert
surgery but not for surgeries lasting for more than a high osmotic pressure. Therefore, for diabetic
1 hour, because of the development of corneal patients a higher osmolarity irrigation solution is
edema.17,18 Lactated Ringer’s solution consists of used to prevent osmotic movement of water into
chlorides of sodium, potassium and calcium and the lens and subsequent development of posterior
sodium lactate. Long-lasting intraocular surgeries subcapsular cataract.25 For vitreoretinal surgeries,
require additional components in irrigating use of oxygenated intraocular irrigation fluid by
solution such as bicarbonate, glucose, glutathione using an in-line oxygenator has been described.26
and adenosine.19 Therefore, the commercially Oxygenated intraocular irrigation fluid facilitates
available complete irrigation mediums contain significantly earlier return of electroretinogram
phosphate, bicarbonate, magnesium, glucose voltage to baseline after vitreoretinal surgery as
and glutathione. Phosphate and bicarbonates compared to unoxygenated BSS plus.27
act as buffers and glucose provides a source The complete irrigation solutions are available
of energy. Glutathione is a peptide that acts in two parts, which are mixed together just before
as antioxidant and helps in maintaining the use and remain stable for the period of surgery.
intercellular junctions. Magnesium is essential The composition of two commercially available
for the functions of ATPase pump in corneal complete and incomplete intraocular solutions is
endothelial cells. Adenosine is not added to the given in Table 19.3.
complete irrigating solutions as it makes the
medium unstable.
In a prospective randomized double-blind trial, EXTRAOCULAR IRRIGATING
comparison of Ringer’s lactate with BSS plus was SOLUTIONS
done in patients undergoing phacoemulsification
surgery for cataract. It was observed that the two Extraocular irrigating solutions are used to remove
solutions were comparable if the time of surgery unwanted substances from the ocular surface. As
was short and limited volume of solution was mostly they are used for short period they do not
used.20 Dextrose bicarbonate Ringer’s lactate require nutrients or specific ion as is the case with
was also shown to provide similar results as intraocular irrigating solutions. However, their
BSS plus for short duration surgeries. As the pH and osmolality is physiologically maintained.
Ringer’s lactate and Dextrose bicarbonate Prolonged exposure to these solutions can cause
Ringer’s lactate are many times cheaper than cellular swelling and damage.28 Composition
BSS plus, they are considered preferred choice of different commercially available extraocular
for short surgeries, especially in developing irrigation solutions is shown in Table 19.4.
countries.20,21 However, in patients that required Extraocular irrigating solutions are used to
longer surgery time and use of large volumes of wash out debris, mucus, purulent discharge and
solution, the reduction in corneal endothelial cell other unwanted material from the ocular surface,
density was significantly higher with Ringer’s removal of foreign body, after tonometry to
lactate.20 The complete irrigation mediums like remove the dye, after gonioscopy to remove
BSS plus are also required for patients with methycellulose and for diagnostic nasolacrimal
compromised corneal endothelium even if the duct irrigation in patients with epiphora. These
surgery lasts for less than 1 hour.22,23 Similarly, solutions can be used to wash eyes after wearing
Table 19.3 Composition of various commercially available intraocular irrigating solutions
Components (mmol/L) BSS (Alcon) AMO endosol BSS plus AMO endosol extra
(Akron) (Alcon) (Akron)
Sodium chloride 109.5 109.5 122.2 109.4
Potassium chloride 10.1 10.1 5.1 4.6
Calcium chloride 4.3 4.3 1.1 1.2
Magnesium chloride 1.5 1.5 1.0 1.9
Sodium bicarbonate 25 22.4
Sodium phosphate 2.8 2.7
Sodium citrate 5.8 5.8
Sodium lactate
Sodium acetate 28.6 28.6
Sodium gluconate
Glutathione disulfide 0.3 0.3
Glucose 5.1 4.6
Table 19.4 Composition of various commercially available extraocular irrigating solutions
Components (%) Eye-stream (Alcon) Eye wash (Levoptik) Eye irrigating wash
(Roberts Hauck)
Sodium chloride 0.64 0.49
Potassium chloride 0.75 0.38
Magnesium chloride 0.03
Calcium chloride 0.048
Sodium acetate 0.39
Sodium citrate 0.17
Sodium biphosphate 0.4
Sodium phosphate 0.45
Sodium carbonate 0.014
Boric acid 1.2
EDTA 0.05
Benzalkonium chloride 0.013 0.005 0.01
contact lens but cannot be used with contact lens VISCOELASTIC AGENTS
in place. They cause irritation and can alter the
lens surface. Preservatives in the solution can Viscoelastic substances are widely used in
get absorbed in the hydrogel lens and then will intraocular surgery. They are viscous solutions
be delivered to corneal surface over a prolonged of high molecular weight substances. Due to the
period causing corneal toxicity. viscosity of solution, they protect and lubricate
the ocular tissue during surgery. Their elasticity Sodium hyaluronate (hyaluronic acid) is
provides protection against the mechanical composed of two monosaccharide units and
damage caused by vibrating instruments. Their is a main component of vitreous humor. It
pseudoplasticity allows safe manipulation has been shown to play an important role in
of the tissue. During surgery they have been inflammation by stimulating neutrophil migration,
shown to reduce the endothelial cell loss.29,30 aggregation and proliferation and promoting
Use of viscoelastic agents during surgery helps wound healing.34,35 Healon® was first introduced to
to maintain the depth of anterior chamber clinical practice in 1979 and since has become an
and protect the newly formed and exposed important component in ocular surgery. Healon®5
surfaces. They are routinely used as adjuncts in (sodium hyaluronate 2.3%, 4 × 10 6 daltons)
cataract surgery, intraocular lens implantation, was used in 1998. It has a higher viscosity but
keratoplasty, glaucoma filtration surgery and its injection and removal after surgery is more
vitreoretinal surgery. These agents are tissue- difficult. In a randomized multicenter clinical trial
protective, non-antigenic and do not interfere with comparing Healon®5 and Healon®, it was observed
wound healing. The use of sodium hyaluronate that retention during phacoemulsification,
as a component of vitreous substitute needed to anterior chamber maintenance during continuous
replace vitreous humor after vitrectomy has also curvilinear capsulorhexis (CCC), and facilitation
been described.31 Küçükerdönmez et al. reported of intraocular lens (IOL) implantation was better
that intraocular injection of hyaluronic acid may achieved with Healon®5 as compared to Healon®,
be useful for stabilizing IOP and vision in patients however, Healon®5 was more difficult to inject
with previous vitreoretinal surgery.32 and remove than Healon®.36 DisCoVisc® due to
The viscoelastic agents can largely be classified its dual nature has been shown to provide corneal
into two classes: cohesive and dispersive. Cohesive endothelial cell protection comparable to Viscoat®
agents are high molecular weight substances with during phacoemulsification and at the same time
highly entangled molecular structure whereas is better retained with shorter removal time as
dispersive agents are smaller molecular weight compared to Viscoat® or Healon®5.37,38
with more straight chain structure. Cohesive While clearing from the anterior chamber,
viscoelastics such as Healon® (sodium hyaluronate sodium hyaluronate can block the outflow
1%, 4 × 106 daltons) and Healon GV® (sodium channels in trabecular meshwork due to its large
hyaluronate 1.4%, 5 × 106 daltons) are useful molecular size and causes post-operative rise in
in maintaining the depth of anterior chamber intraocular pressure. Therefore, after completion
and are easy to remove after surgery whereas of surgery, sodium hyaluronate is removed from
dispersive agents such as Viscoat ® (sodium the anterior chamber.39,40 The residual amount can
hyaluronate 3%, 5 × 105 daltons—chondroitin cause postoperative inflammation and allergy.
sulfate 4%) provide effective coating over Corneal haze sometimes may occur due to altered
corneal endothelium and are difficult to remove. water balance in the cornea causing change in its
DisCoVisc® (sodium hyaluronate 1.6%, 1.7 × refractive index.41 Sodium hyaluronate can also
106 daltons—chondroitin sulfate 4%) is a new cause crystalline deposits on intraocular lenses.42
viscoelastic agent that does not fit into either
category as it has viscosity similar to Healon®, but Hydroxypropyl methylcellulose (HPMC),
is dispersive like Viscoat®.33 Sodium hyaluronate chondritin sulfate and type IV collagen are
is also available in combination with lidocaine the other viscoelastic substances used during
as VisThesia topical (sodium hyaluronate 0.3%, intraocular surgery. HPMC is a derivative
lidocaine 2%), for corneal hydration and topical of cellulose, chondroitin sulfate is similar to
anesthesia, and VisThesia intracameral (sodium hyaluronic acid in its chemical structure and
hyaluronate 1.5% and lidocaine 1%), for cohesive collagen is a protein found in the connective
viscoelastic use and intracameral anesthesia. tissue. The uses and adverse effects of these
agents are similar to those of sodium hyaluronate. with the release of acetylcholine from nerve
Combinations of viscoelastic agents are also fibers, blocks neuromuscular transmission and
available for use. relieves localized muscle spasm. The effect is
dose-dependent and lasts for up to 9 months.
Once injected into the muscles it is not absorbed
SURGICAL MIOTICS systemically. The dose needs to be individualized
Acetylcholine (ACh) chloride solution (1:100) is and sometimes multiple injections are necessary.
applied directly to exposed iris to induce miosis Response also depends upon the type and
during surgical procedures such as cataract severity of disorder. Botulinum toxin is used
extraction, keratoplastry, iredectomy. ACh is in the treatment of blepharospasm, strabismus,
ineffective if applied topically but is safe and nystagmus, hemifacial spasm, lower lid entropion
effective for intraocular use. However, its effect and corneal ulcer resulting from exposure. Use of
is short-lasting as it is quickly destroyed by botulinum toxin is associated with several adverse
effects such as diplopia, ptosis, scleral perforation,
acetylcholinesterase.
Carbachol, a direct-acting cholinomimetic reduced accommodation, hemorrhage, pupillary
agent, produces long-lasting miosis. Its 0.01% dilation, dry eye and local tissue reactions.
solution is applied by gentle irrigation in a dose
of 0.5 mL. Longer acting and topically effective TRYPAN BLUE
miotics like pilocarpine can be used to produce
miosis immediately after surgery but they cause Trypan blue is a dye that selectively stains the
increased postoperative pain and inflammation. connective tissue structures such as anterior lens
capsule. It can be used as an aid in ophthalmic
surgery as it stains only the anterior capsule,
SURGICAL ENZYMES which can be visualized against unstained interior
Hyaluronidase, an enzyme often added to of the lens. The dye is immediately removed from
local anesthetic solutions to produce enhanced the anterior chamber and its use is contraindicated
a n e s t h e s i a a n d a k i n e s i a . T h e e n z y m e if non-hydrated hydrophilic acrylic lens is planned
depolymerizes the hyaluronic acid, which is a to be inserted as it stains the lens. During small
component of connective tissue and acts as tissue incision cataract surgery, trypan blue has been
cement. Break down of hyaluronic acid allows shown not to affect the IOP in immediate and
early post-operative period.43
easy and rapid spread of anesthetic solution
through the tissue. It is added to local anesthetic
solutions for retrobulbar and peribulbar block in GROWTH FACTORS
a dose of 75 units per 10 mL of solution.
Urokinase is used to irrigate hyphema and Growth factors are endogenous polypeptides that
in cases of retinal artery and vein occlusion. are known to promote wound healing. Growth
The conversion of plasminogen to plasmin by factors regulate normal turnover of a variety of
urokinase causes degradation of plasma proteins, cells including corneal epithelium. They play a
fibrinogen and fibrin clots. role in ocular healing by stimulating cell division
and migration of corneal cells, synthesis of
extracellular matrix in cornea and chemotaxis.44-46
BOTULINUM TOXIN
Epidermal growth factor (EGF) has been
Botulinum toxin is derived from bacterium shown to promote corneal wound healing
Clostridium botulinum. Its serotype A is used following mechanical and chemical injury.
in therapeutics. The botulinum toxin interferes This effect of EGF is mediated by cyclic
adenosine monophosphate (cAMP)-dependent MITOMYCIN C
cell proliferation and differentiation. It is a dose-
dependent effect and has been observed in corneal Mitomycin C is an antineoplastic antibiotic agent,
epithelium and endothelium.47,48 EGF has not been which is now used widely in ophthalmic practice.
used widely in clinical practice as the mitogenic It is isolated from the soil bacterium Streptomyces
properties of EGF that promote wound healing caespitosus. It affects rapidly dividing cells such
are non-specific and, therefore, may also promote as fibroblasts in a healing wound by interfering
undesired growth of other tissues. Moreover, with DNA synthesis, RNA transcription and
EGF also has angiogenic properties and has been protein synthesis. The cell cycle is most affected
found to be elevated in patients with neovascular at late G-I and early S-phase. It is available as
glaucoma.49 2 mg/mL solution and is further diluted for use
Fibroblast growth factor (FGF), like EGF is in sterile water at neutral pH. It is inactivated
known to promote corneal wound healing after at acidic pH. Due to its hydrophobic nature, it
mechanical or chemical injury by stimulating penetrates tissue easily.
cell division, migration, differentiation and Subconjunctival or scleral application of
chemotaxis.50 The exact mechanism of action of mitomycin C at a concentration of 0.2–0.4 mg/
FGF is not known but it seems to be associated mL is used intraoperatively during glaucoma
with specific receptors linked to diacylglycerol- filtration surgery to prevent scarring of filtering
inositol phosphate second messenger system. FGF bleb as it inhibits fibroblast growth. After
is also associated with neovascular glaucoma due pterygium excision also it is applied at the same
to its angiogenic properties.51 concentration to prevent recurrence. In patients
Transforming growth factors (TGFs) α and β have undergoing dacryocystorhinostomy, mitomycin
been isolated from various parts of ocular tissue. C is used to suppress fibrous proliferation and
They promote wound healing by promoting cell scar formation under the flaps near osteotomy
division, migration and differentiation in corneal sites. Topical mitomycin C has been shown
epithelium, endothelium and stroma.50 TGF β2 to reduce post-operative adhesions following
may also enhance the closure of macular holes. squint surgery. It has also been used to prevent
TGFs have not been widely used so far in clinical development of corneal haze after laser surface
practice due to their non-specific action and TGF ablation in refractive surgeries. It prevents
β2 also seems to play a role in the development of recurrence of localized conjunctival-corneal
proliferative diabetic retinopathy.52 intraepithelial neoplasia.
Other growth factors that can promote ocular Complications associated with the use of
wound healing include Insulin-like growth factor mitomycin C include necrotizing scleritis, scleral
(IGF), fibronectin and keratinocyte growth ulceration, perforation, uveitis, cataract, glaucoma,
factors (KGF). IGF has been shown to promote symblephron formation, photophobia, lid edema
neovascularization and fibronectin promotes and ocular pain. Its use is contraindicated in one-
cataract development.53 eyed and very elderly patients.
C. Sterilization, Disinfection and Antiseptics in

Ophthalmology
Lwin Lwin Nyein
OVERVIEW spores. The objective of sterilization is to remove

or destroy microorganisms, since they cause
Medical equipments and surgical instruments are contamination, infection and decay. The purpose
devices that are essential for the care of patients for sterilization, the material to be sterilized and
and their use in preventive medicine is inseparable the nature of the microorganisms that are to be
from diagnostic procedures and therapeutic removed or destroyed determines the choice of
practices. Aseptic techniques in hospitals involve methods of sterilization.55 Sterilization processes
systematic, appropriate and continued effort to involve chemical and biological methods such as
eliminate pathogenic microorganisms from the pressure, temperature and others.
patient’s environment to prevent infection. The Disinfection is a process, chemical or physical,
basis for aseptic procedures rests on fundamental that destroys viable microorganisms excluding
concepts related to the mode of transmission, bacterial spores. The most important factor in
virulence, and destruction of microbes and the using disinfectant is its concentration, time of
resistance or susceptibility of the host. These basiccontact with the disinfectant and precautions
concepts are firmly established in microbiology, advised by the manufacturer. Several methods of
epidemiology and general surgery: specialized disinfection are available, but standardization and
considerations determine their application to uniformity throughout a hospital setting is essential.
ophthalmology.54 Disinfection is not a substitute for sterilization.
Decontamination, disinfection and sterilization High-level disinfection (HDL) is a process that
are basic components of eye care services. Lack eliminates all microorganisms except some
of knowledge or negligence in standard practices bacterial endospores from inanimate objects
would result in hazardous effects, as sterile by boiling, steaming or the use of chemical
instruments and environment are essential for disinfectants.56
The compounds commonly used in the
successful eye care services. In ophthalmic
opthalmic practice are listed in Table 19.5
practice, major hospital associated infectious
diseases are minimal as the hospital stay of a
patient rarely exceeds 48 hours. Moreover, such METHODS OF STERILIZATION
infections are preventable.
The most common methods used for sterilization
Currently, the concept of sterilization in
are:
ophthalmology is focused towards safe aseptic
1. Dry Heat: It kills microorganisms by
practices and the range of techniques and destructive oxidation of cell constituents. It
compounds used to achieve a clean surgical is effective for sterilizing metal instruments
environment has greatly increased. as by conduction, the heat reaches all surfaces
of the instrument to be sterilized. It cannot
DEFINITIONS be used for plastic and rubber items as
temperature used in hot air oven (160–170° C)
Sterilization is defined as the method that destroys is too high and penetrates materials slowly
all viable microorganisms including bacterial and unevenly.
Table 19.5 Compounds commonly used for antisepsis, disinfection and sterilization in ophthalmic practice
Compounds Mechanism of action Properties Antiseptic Disinfection Sterilization Uses in ophthalmic

action practice
Alcohols Precise mechanism Rapid broad spectrum + + Hand washing and

Ethyl alcohol unknown but act by antimicrobial activity as antiseptic before
and isopropyl causing membrane but not sporicidal surgery
alcohol damage and To clean skin or
protein denaturation surfaces
Aldehydes Affect enzyme systems High antimicrobial + + To sterilize ophthalmic
Glutaraldehyde activity including instruments
and Formaldehyde mycobacteria, viruses and
spores
Less active at an acidic pH
Anilides Destroys the Active against Gram-negative + Used mainly in soaps
Triclocarbon cytoplasmic membrane bacteria and deodorants but
rarely clinically
Biguanides At higher Broad spectrum but not + Used for preoperative

Chlorhexidine concentrations, sporicidal, poor effect on hand washing or for
increases membrane mycobacteria, and variable preoperative skin
PHMB permeability and antiviral effect preparation in patients
(Polyhexamethylene coagulates intracellular Activity is pH dependent and with iodine allergies.
Biguanide) contents reduced in the presence of Used in a specialized
organic matter. The most formulation
widely used biocide (PHMB) for the
treatment of
Acanthamoeba
keratitis
Contd...
Miscellaneous Drugs
259
Contd...
Halogen Releasing Highly active oxidizing + Most widely used to

Agents agents. Inhibit disinfect tonometer
Sodium hypochlorite DNA synthesis Disinfect blood heads
spillages containing
HBV and HIV and sporicidal at high
concentrations +
Iodine +
Wide scope of antimicrobial activity
including spores +
Iodophors, e.g. Surgical skin preparation
povidine-iodine Better tolerated than iodine and leaves a and preoperative
depot of active iodine, handwashing
therefore, leading to a Rarely used now
persistent effect
Silver Compounds Bind to membrane Broad spectrum of activity + Rarely used now
Silver sulfadiazine bound enzymes via thiol Traditionally used as
and silver nitrate groups prophylaxis and for the
treatment of ophthalmia
neonatorum
Peroxygens Oxidizing agent and Good antifungal and antiviral properties. + + Commonly used in contact
Hydrogen peroxide breaks DNA strands Need higher concentrations and lens disinfectant solutions
longer exposure for sporicidal activity.
Environment friendly as it breaks down
to water and oxygen but needs a
stabilizer to prevent
decomposition
Phenols and Affects microbial Broad spectrum of activity and good + + Used as preoperative hand
Bisphenols membranes sporostatic agent. Most commonly used antisepsis and cleansing
e.g. tricloscan as a preservative or as an antiseptic Used in treating
towel. Inactivated by anionic MRSA carriers preoperatively
surfactants, e.g. soap
Quaternary Affects microbial Broad spectrum of activity and good + Most widely used as a
Ammonium cytoplasmic membranes sporostatic agent. Most commonly used preservative in eyedrops
Compounds as a preservative or as an antiseptic An active ingredient in
e.g. benzalkonium towel. Inactivated by anionic surfactants, some contact lens soaking
chloride e.g. soap solutions
2. Moist Heat: It kills microorganisms by (hospital-acquired) infections and spread of
coagulation and denaturation of the enzymes multi-drug resistant microorganisms, and has
and structural proteins. It is most commonly been recognized as a significant contributor to
used and an effective method of sterilization. outbreaks.56 The most important procedures for
Steam under increased pressure is more preventing such infections include the following:
efficient sterilizing agent than hot air oven 1. Hand washing should be done before:
as it provides greater lethal action, shorter –– Examining (direct contact with) a patient; and
sterilization time and penetrates porous –– Putting on sterile or high-level disinfected
material effectively. surgical gloves prior to an operation, or
3. Chemical Method: Glutaraldehyde and examination for routine procedures.
formaldehyde are examples of chemical 2. Hand washing should be done after:
sterilant. Both are used for instruments that –– any situation in which hands may become
will not tolerate heat sterilization such as contaminated, such as:
laparoscopes. They are irritant to skin, eyes
–– Handling soiled instruments and other
and respiratory tract.
items;
Compounds that are commonly used in
ophthalmic practice are summarized in Table 19.5. –– Touching mucous membranes, blood or
While ensuring safe sterilization systems, other body fluids (secretions or excretions);
ophthalmologists should be more concerned –– Having prolonged and intense contact with
about properly preparing the surface of the eye, a patient; and
where the majority of flora is found and which –– Removing gloves.
commonly is the biggest source of infection. 3. In high-risk areas, an antiseptic liquid hand-
Proper sterilization, coupled with appropriate washing agent (such as an iodophor or
cleaning of eye instruments; use of well-designed chlorhexidine gluconate) should be used, both
trays, packaging, and sterilization indicators; before and after direct contact with patient.
meeting manufacturer’s recommendations with High-risk areas include cornea clinic and
regard to time, temperature, and pressure; and minor operation theater.
effective transfer to the site of use, is a highly 4. General patient care areas, outpatient clinics
effective means of sterilization in ophthalmic and clinical laboratories require only a general
surgery.57,58 liquid hand-washing agent.
5. Bar soap and towels should not be used for
multipatient purpose.55
METHODS OF PREVENTING
CONTAMINATION IN OUTPATIENT Needle Stick/Splash Policy
SERVICES Splash policy is to be strictly adhered to avoid
Sources of infection to outpatients are mainly due transmission of infection through accidental splash
to contamination on the surgeon’s and paramedic’s of a needle stick with blood contamination, body
hands, tonometer, slit lamp and opened old fluids, mucous membranes or non-intact skin.
medication bottles. Patients in contact with The needle stick injuries should be thoroughly
contaminated ophthalmic diagnostic instruments cleaned, and the affected area rinsed with soap
like the tonometer and slit lamp are at high risk of and water.55
getting ocular infections due to bacteria and viruses.
Disinfecting Tonometers
Hand Hygiene 1. Dry heat
Failure to achieve appropriate hand hygiene is 2. Mechanical cleaning with disposable wipe/
considered to be the leading cause of nosocomial sterile gauze.
3. Wipe with gauze soaked in alcohol or chemicals are designed to create such environment by
like hydrogen peroxide and merthiolate. controlling four main sources of infection:
4. Soaking in chemicals like 70% isopropyl the patient, surgical staff, equipment and the
alcohol, 1:1000 merthiolate, 3% hydrogen operating room environment. Specific techniques
peroxide and 1:10 diluted house hold bleach are established through following procedures:
(sodium hypochlorite).55 Patient considerations: skin cleaning pre-
operatively, skin antisepsis and wound

Disinfecting Slit Lamp covering
Surgical staff considerations: hand hygiene
1. Mechanical cleaning with disposable wipe/ (hand washing and/or hand rub with waterless,
sterile gauze. alcohol-based antiseptic agents); use and
2. Wipe with gauze soaked in alcohol or chemicals removal of gloves and gowns
like hydrogen peroxide and merthiolate.55 Equipment and room preparation consid-
erations: traffic flow and activity pattern as

PREVENTIVE METHODS IN THE well as housekeeping practices and decon-
tamination, cleaning and either sterilization or
OPERATION THEATER high-level disinfection of instruments, gloves
Post-operative infection remains a major cause and other items
Environmental considerations: maintaining
of morbidity among patients undergoing surgery.
Maintenance of strict asepsis is essential if post- an aseptic operating field and using safe
operative infections and their consequences operating practices and techniques.44
are to be minimized. Such infections can be
either endogenous or exogenous. Factors PREVENTION IN HIGH-RISK AREAS/
associated with transmission of infective material
exogenously in a hospital are: use of unsterile STAFF
equipment, presence of shedders of pathogenic Healthcare professionals are at high risk of
microorganisms amongst hospital personnel, infection: anesthetists, surgeons, laboratory
contaminated environment and contaminated personnel, operating-room staff and places that
surfaces.55 are exposed to contaminated blood and body
The ophthalmic operating room (OR) is a fluids. Preventing accidents (needle sticks) and
highly specialized unit where strict asepsis needs other blood and body fluid exposures are the
to be maintained because of the fear of post- primary means of preventing transmission of HIV
operative infections including endophthalmitis. or HCV/HBV.
The incidence of post-operative endophthalmitis
sporadically or as mini-outbreaks especially in
Hepatitis
ophthalmic camps has increased. It is possible and
feasible to prevent such infective complications Hepatitis is a hospital-acquired-infection in health
with proper disinfection and sterilization routines. care workers and hence prevention against it is
Post-operative endophthalmitis, external essential. The major sources of infections are
ocular infections such as conjunctivitis, infections needle sticks and blood spills.
transmissible through corneal transplantation, For HBV, an effective vaccine has been
hepatitis and HIV are major hospital-borne available for nearly 20 years. Personnel working
infection and preventive measures should be taken in high risk areas should be given information
in order to avoid them. about hepatitis B and the risk of developing the
Preventing infections following an operation disease. The decision to have hepatitis B vaccine
is a complex process. Surgical aseptic techniques administered shall be left to the employee.
Priorities for the administration of hepatitis B STERILIZATION IN OPHTHALMIC
vaccine to employees shall be developed by the PRACTICE: CURRENT STATUS
infection control committee.44
Health and safety measures should be well
Human Immunodeficiency Virus (HIV) informed to the personnel in the operation
theater, staff in direct contact with patients or
The plan for assessing the risk of accidental those involved with disposal of infective waste
exposure to HIV is similar to that for HBV. Since materials, so that they can protect themselves and
there is no vaccine against HIV, post-exposure others from infection. Since there are substantial
prophylaxis is much more complicated; therefore, epidemiological evidences of diseases caused
the decision to recommend it needs to be based by hospital borne infection, there should be
on a careful assessment of the injury. regular monitoring of disinfectant and sterility
The suggested steps for managing an injury procedures by “Infection Control Committee
are as follows: (ICC)” with an Infection Control Nurse and
Direct contact of skin and mucous membranes
adequate surveillance. Since patient care is a
with blood, blood products, secretions, wastes priority, infections due to negligence should not
and tissues of patients should be avoided occur. It is highly essential to take preventive
Regardless of the use of gloves, hands should measures to maintain hygienic and sterile
be washed routinely environment for eye care service.54
Gloves should be worn for contact with moist One of the commonly used methods of
body substances sterilization by the ophthalmologist is the “flash
If soiling of cloths with moist body substances sterilization”. The Center for Disease Control
is anticipated, gowns or aprons should be used and Prevention (CDC) guideline are used as a
Masks or goggles should be worn guide for disinfection and sterilization. In 1999,
If infection requiring a private room is this guideline described flash sterilization as
mandated, then it should be arranged having very limited applicability for sterilizing
Care should be taken to avoid needle splash, instruments. At that time, flash sterilization was
while handling needle sticks on patients commonly used when an instrument was dropped.
Reusable items should be reprocessed and It was then ‘flashed’ for immediate re-use. Some
kept in the soiled utility room.55,56 of the ophthalmologists used this method not as
an exception but often as the sole method. Such
Infective Waste Disposal process appeared to violate (CDC) guidelines and
triggered a closer look into ophthalmologist’s
Infective waste should be incinerated or should use of steam sterilization and the entire process
be autoclaved prior to disposal. Sharp items like of cleaning, disinfecting, and sterilizing surgical
needles, scalpel blades that could cause injury, instruments.
should be placed intact into puncture-resistant In 2008, the CDC updated its stance in its
containers. Needles should not be recapped, bent, “Guideline for Disinfection and Sterilization
broken or manipulated by hand, in order to avoid in Healthcare Facilities”, stating: “Correctly
needle-stick injuries. performed flash sterilization is an effective process
Strict rules should be followed for waste for the sterilization of critical medical devices.”
disposal in a hospital. The paramedics should be The flash method also called steam sterilization
aware of the specific color codes of bags used for is the most common form of sterilization used
disposal of infective waste.55 by ophthalmologists, and the infection rate it
carries in ophthalmic surgeries is very low. In correct sterilization methods should be followed;
fact, while ensuring safe sterilization systems, a sufficient number of instrument sets should be
ophthalmologists should be more concerned available to allow adequate time for cleaning and
about properly preparing the surface of the eye, sterilizing between procedures and all employees
where the majority of flora is found and which should be trained uniformly regarding the
commonly is the biggest source of infection.58,59 handling and cleaning of the surgical instruments.
It is critical that hospitals and surgical centers Under these circumstances there can be no
keep and follow the policies and procedures justification for the use of method which does
regarding the sterilization and disinfection. In not achieve absolute sterility of instruments,
addition, other ancillary procedures are also materials, and solutions. Whatever may be the
necessary to control nosocomial infection. It is method of sterilization in ophthalmology, the
important that administrative controls should objective is to stress the indispensable nature of
be implemented; policies and instructions for aseptic technique in ocular surgery.
D. Contact Lens Care Systems

Puneet Agarwal
OVERVIEW defense mechanisms impairs clearance of debris

and microorganisms from the ocular surface
All types of contact lenses except the daily and predisposes to infections. The occurrence of
disposable and extended wear lenses require contact lens related adverse effects has also been
careful maintenance with disinfectant and partly attributed to hypoxia. Currently available
cleaning solutions. Commercial development of high oxygen permeability lenses have reduced
solutions for contact lens care started emerging the incidence of adverse effects.62-64 Microbial
in 1940s with increasing usage of rigid contact keratitis is the most serious contact lens related
lenses (polymethylmethacrylate, PMMA complication.65-67
lenses). Initially two types of solutions, i.e. Besides facilitating the contact lens wear and
“wetting” and “soaking” solutions were used. preserving the optical and physical properties
In 1970s, hydrogel lenses became popular and of lenses, one of the most important objectives
it was observed that they had greater affinity of using contact lens solutions is to reduce the
for surface deposits. Therefore, several newer risk of infection. Cleaning contact lenses before
forms of contact lens care systems such as disinfection is extremely important because
dual, triple and multipurpose solutions were the adhered debris can cause lens distortion,
developed. Moreover, the enzymatic cleaners discoloration, discomfort and damage to ocular
were introduced for more effective cleaning of surface. Prior cleaning also enhances disinfection
lenses and efforts were made to develop soft by reducing the contamination. The efficacy
hydrogel lenses that are resistant to surface of disinfectant solutions is regulated by the
deposits. As a result in 1990s very high oxygen International Organization for Standardization–
permeability soft silicone hydrogel lenses were ISO. All solutions must pass the recommended
developed that adsorbed less proteins. tests prior to commercialization. In practice, the
Wearing contact lenses renders eye at a greater efficacy of disinfectant solutions is related more
risk of acquiring infections as compared to non- to the user’s compliance rather than the type of
contact lens wearers. According to Brennan and solution used. Rewetting and saline solutions
Coles, the risk of bacterial keratitis is 60 times are used to enhance ocular comfort and reduce
higher in contact lens wearers as compared to non- contamination.
wearers.60 According to a survey done over a period Daily enzymatic cleaning is not required
of 2 years in public hospitals of Singapore, infective for disposable soft hydrogel and soft silicone
keratitis secondary to soft contact lens wear was hydrogel lenses but is optional for rigid lenses
found to be the most common complication. Other (Tables 19.6 and 19.7).
complications included epithelial keratitis and
allergic conjunctivitis.61 The reason for higher CLEANING SYSTEMS
risk of infection is primarily due to interference
with the normal defense mechanisms on the All contact lens users are advised to clean the
ocular surface such as flow of tears, blinking, lenses after each use. During wear, lenses get
antibacterial enzymes, immunoglobulins in tear contaminated by lipid, proteins and mucus in
film and presence of ocular surface mucus as a tears, pollutants and cosmetics. The cleaning
physical barrier. Interference with the normal systems that are in use include:
Table 19.6 Desirable properties and usage of contact lens solutions
Rigid lenses Soft hydrogel lenses Soft silicone hydrogel lenses

Daily cleaning Required Required* Required
Daily disinfection Required Required* Required
Desirable properties in all 1. Be sterile and not a source of infection
contact lens care solutions 2. Should not interact with the material of lens and cause changes in optical and
physical properties of lens
3. Should not discolor the lens
4. Should be nonirritant and nontoxic to eyes
5. Easy and user-friendly application
*Daily disposable types of lenses do not require daily cleaning and disinfection.
1. Surfactant cleaners alone.69 Sugihara, et al. described a cholesterol

2. Enzymatic cleaners esterase from Pseudomonas aeruginosa that
Surfactant cleaners help to remove loose can be utilized for cleaning lipid-stained contact
proteins and debris from the lens surface. They lenses.70 Methyltrypsin loaded poly (D, L-lactide-
act as detergents, form micelles with the lipid coglycolide) nanoparticles have been shown to
droplets and clean the lenses by solubilizing provide effective lens cleaning and acceptable
the debris. Some cleaning preparations also ocular tolerance.71 The cleaning systems are
contain substances like isopropyl alcohol as a available as tablets, which can be dissolved
lipid solvent and preservative. Other surfactant in either a multipurpose solution or hydrogen
solutions contain preservatives like sorbic acid peroxide. Liquid formulations are also available
and potassium sorbate to prevent microbial that can be added to the disinfectants. The use
contamination of the solution. Thimerosal and of enzymatic preparations has declined due to
chlorhexidine are not in use now because of the increased popularity of frequently replaced soft
hypersensitivity reaction that they can cause. lenses.
Besides a preservative, many cleaning solutions
also contain a chelating agent like EDTA, which
helps to chelate calcium ions. Calcium ions DISINFECTION SYSTEMS
facilitate adhering of proteins to lens surface. To Disinfection is the primary objective of contact
obtain a stable pH, phosphate or borate buffers are lens care. The earliest methods for disinfecting
also added to the cleaning solutions. the lens relied on the use of heat. Heating as a
Enzymatic cleaners help in removing closely method of disinfection required exposure to a
adherent proteins from the lens surface that temperature of 80°C for 10 minutes. Although
cannot be removed by surfactant solutions. the method was very effective, it carried a number
Cleaning of soft lenses with enzymatic cleaners of disadvantages like altered lens parameters
helps in removing the mucin coating, which and denaturation of proteins leading to reduced
plays a significant role in the pathogenesis of visual acuity and ocular surface reactions
contact lens-associated Pseudomonas corneal such as giant papillary conjunctivitis. The
ulceration.68 Enzymatic cleaning solutions contain method used unpreserved saline, which increased
enzymes like papain, pancreatin or subtilisin-A. the chances of microbial contamination and,
Lenses cleaned weekly with pancreatin containing moreover, the method was inconvenient to users.
enzymatic cleaners in addition to daily cleaning Subsequently, microwave irradiation was used.
showed less deposits, more comfort and less The method was cheap and effective, provided
complications as compared to daily cleaning clinically insignificant parameter changes but
Table 19.7 Commonly used contact lens solutions: constituents and properties
Hydrogen peroxide Single disinfectants Dual disinfectants
Clear Care Oxysept Complete Renu fresh Renu Biotrue Opti-free Opti-free
easy rub sensitive express replenish
Maker CIBA AMO AMO Bausch and Lomb Bausch and Bausch and Alcon Alcon
Vision Lomb Lomb
Preservatives 3% H2O2 3% H2O2 PHMB PHMB 0.0001% PHMB PHMB 0.00013% PQ-1 PQ-1 0.001%
and 0.0001% 0.00005% PQ-1 0.0001% 0.001% MAPD
concentration MAPD 0.0005%
0.0005%
Chelators None None EDTA EDTA EDTA EDTA EDTA None
Surfactant Pluronic HPMC Poloxamer 237 Poloxamine hydranate poloxamine Hyaluronan, Tetronic Tear Glyde
17R4 poloxamine 1304
Buffer Phosphate Phosphate Sodium Boric acid, sodium Boric acid, Boric acid, Boric acid, Sodium
phosphate borate sodium sodium citrate sodium borate,
borate citrate sodium citrate
pH 6.7 not tested 7.2 7.3 7.3 7.5 7.8 7.8
Regimen Rinse only Rinse only Rub/rinse Rub/rinse Rub/rinse Rub/rinse Rinse only Rinse only
Minimum soak 6 hours 6 hours 6 hours 4 hours 4 hours 4 hours 6 hours 6 hours
time
Minimum storage 7 days 7 days 30 days 30 days 30 days 30 days 30 days 30 days
Miscellaneous Drugs
267
required availability of a microwave oven. Use of Hydrogen peroxide is a strong oxidizing agent
ultraviolet rays and ultrasonic systems was also and has a broad-spectrum antimicrobial action
suggested but the efficacy of these systems was against bacteria, fungi and yeast. It produces
limited. Because of the problems associated with hydroxyl free radicals, which damage the essential
these systems, newer methods were introduced cell proteins and lipids. A solution of 3% H2O2
that can disinfect the lens without altering its can kill the trophozoites of Acanthamoeba within
physical or chemical structure and are suitable 3 minutes and cysts after 9 hours of storage.
to eye. The early disinfectant solutions consisted Hydrogen peroxide based solutions also help in
of a combination of chlorhexidine gluconate removing protein deposits on the soft lenses.72 It
and thimerosal. Chlorhexidine kills bacteria and is stabilized with phosphates because it breaks
yeast by attacking their cell wall. Thimerosal down on storage. H 2O 2 is toxic to eyes and,
is more effective than chlorhexidine against therefore, after overnight disinfection/cleaning,
fungi. Although, the use of these agents was it must be neutralized before putting the lens in
convenient but they were adsorbed on the lens the eye. Failure to neutralize before insertion into
surface and caused hypersensitivity reaction. the eye causes ocular pain and trauma. Thus, this
After repeated use of these agents the lens disinfection system is a two step process and
becomes uncomfortable to eye. These solutions is highly effective. One step H2O2 disinfection
are now superseded by others that provide similar systems are also available now, which do not
convenience and efficacy with less adverse require the second step of neutralization. They
effects. The newer systems require overnight contain an in-built neutralizing agent capable
storage of lenses in the disinfectant solution. of converting H 2O 2 into water. The one step
In 1980s, chlorine releasing systems were very systems are less efficacious than two step
popular but later on were found to be associated systems and allow regrowth of microbes upon
with microbial keratitis. Currently, available prolonged storage due to decomposition of
disinfection systems are required to pass ISO/ H2O2. Tablet-based one step disinfection systems
DIS 14729 standard for antimicrobial efficacy. neutralize at a slower rate compared to disc-
The regulation requires 1 million organisms/mL based peroxide systems.73 Although the two step
challenge (6 log units) and the solution must be H2O2 disinfection systems are highly effective
efficacious in reducing the growth of: in terms of disinfecting lenses, their popularity
1. The following bacteria by 99.9% (3 log) in is much less due to the inconvenience of using
stated soaking time extra procedures.
a. Staphylococcus aureus Multipurpose disinfecting solutions (MPDS)
b. Pseudomonas aeruginosa are most popular as they eliminate the need
c. Serratia marcescens. for the use of multiple care systems. They
2. The growth of following fungi by 90% (1 log) can be used for cleaning, disinfection, rinsing
in stated soaking time and storage. 74 Several antimicrobial agents
a. Candida albicans have been used in MPDS. Polyhexanide or
b. Fusarium solani polyhexamethylene biguianide (PHMB) was
one of the first preservatives used. It is used in a
The current standards do not include testing concentration range of 0.5–5 ppm. PHMB acts by
against Acanthamoeba and, therefore, thorough causing disruption of bacterial cell membrane. It
cleaning seems to be the best protection against is chemically similar to chlorhexidine but has a
this organism. Two types of disinfecting/cleaning large molecular weight. Because of the larger size
solutions are in use: it fails to penetrate into the lens matrix, thereby
1. Hydrogen peroxide (H2O2) solutions reducing the chances of toxic hypersensitivity
2. Multipurpose disinfecting solutions (MPDS) reactions. The ocular comfort depends upon the
formulation and concentration of PHMB used.75 ocular discomfort, which is the primary cause of
Staining by PHMB is much higher especially discontinuation of contact lens wear. They provide
with group II lenses as compared to another comfort for about 6 hours. Their mechanism of
antimicrobial - polyquad.76-78 providing ocular comfort is uncertain as they have
Polyquad is the largest molecule used as been shown not to enhance the pre-lens tear film.
preservative with molecular weight of 5000. The The single-dose forms are free of preservatives
incidence of toxic hypersensitivity is minimal but but multiple-dose forms contain preservatives to
it has higher affinity for methacrylic acid and less prevent microbial contamination of the solution.
efficacy against Acanthamoeba. Some of the rewetting solutions contain viscosity
One of the newer disinfectants used is sodium enhancers to increase the ocular residence time of
chlorite (NaClO 2 )/peroxide (H 2 O 2 ) system. the solution and, therefore, to provide prolonged
Sodium chlorite generates chlorine dioxide which ocular comfort. Other components of rewetting
effectively kills Gram-positive and negative solutions include sodium chloride and buffering
bacteria, yeast and fungi and subsequently breaks agents.
down into salt, water and oxygen. The solution is
safe and non-toxic to corneal epithelium.79
Alexidine is another newly introduced anti SALINE SOLUTIONS
microbial agent for MPDS. It is a bis-biguianide
and acts by disrupting the microbial cell membrane Saline solutions are used to rinse the lenses
like polyhexanide. It has shown efficacy against before insertion. The user of H2O2 disinfection
Acanthamoeba and is non-irritant to the eyes.80,81 systems require saline solution to avoid stinging
In addition to antimicrobial agents, MPDS also at insertion. These solutions are especially of use
contain a surfactant. Some of the surfactants used for beginners as they need to handle the lenses
in MPDS include poloxamine, poloxamer-237 and more for insertion and can contaminate lenses
pluronic F-127. Other ingredients in MPDS may by fingers. Rinsing helps to remove microbes
include EDTA as a chelating agent and buffers to from the surface of lenses and, therefore, reduces
stabilize the pH. Some studies have shown that chances of infections. Unpreserved saline
MPDS containing boric acid buffers downregulate solutions are not recommended as they are likely
expression of membrane associated mucins to be associated with higher incidence of infection.
and enhance cytotoxicity 82,83 whereas others These solutions are buffered to maintain a stable
have shown that cytotoxic effects of solutions pH. Single-dose forms are free of preservatives
containing boric acid cannot be attributed to but multi-dose forms contain preservatives to
boric acid but are an outcome of the unique prevent contamination of the solution.
combination of all ingredients.84 Some of the
newer solutions also contain a viscosity enhancer
like hydroxypropyl methylcellulose for improved THE LENS STORAGE CASE
ocular comfort or a sequestering agent to reduce
The lens storage case is an important component
protein deposition. MPDS do not decompose
of contact lens care system, which stores the lens
and, therefore, provide continued disinfection.
and the disinfecting solution. Significantly high
The efficacy of MPDS is much higher than the
proportion of contact lens cases show microbial
one-step H2O2 disinfection systems.
contamination, which has not been found to be
related to the type of solution used. Microbial
REWETTING SOLUTIONS contamination of contact lens cases reduces the
efficacy of disinfectant solution. Long-term use of
Rewetting solutions also known as ‘lubricants’ a particular solution allows build-up of naturally-
or ‘comfort drops’ have been used to reduce resistant microbes that can survive in the presence
of that disinfectant. Use of H 2O2 disinfection peroxide between uses also effectively removes
systems allows the growth of bacteria capable the biofilm, reducing the risk of infection.85
of producing catalase. This catalase hydrolyses Increasing use of daily disposable and extended
the H2O2 and facilitates bacterial growth. Lack wear lenses has reduced the requirement of contact
of compliance in keeping the lens cases clean lens solutions but still a large number of contact
predisposes to ocular infections. Rinsing the lens lens users require these solutions. Unfortunately,
cases with disinfecting solution and leaving it open the compliance with their use is poor and,
to air dry may help in reducing the contamination. therefore, physicians need to emphasize the proper
Rubbing and rinsing with a disinfecting solution use of these solutions in accordance with the
followed by wiping the silver-impregnated cases instructions provided by the manufacturer. Regular
has been shown to be effective in removing replacement of old cases with the new ones is the
biofilms. Resoaking the cases in hydrogen best alternative.
E. Nutritional Supplements
Sushma Srivastava, Igor N Iezhitsa, Srikant Gaur
OVERVIEW Zinc
Nutrition plays an important role in keeping Zinc is the most abundantly found trace metal in
the eyes healthy and in maintaining clear the human body. It is a constituent of about 25
vision. A balanced quantity of both macro and enzymes involved in digestion and metabolism
micronutrients is needed for general and visual and aids to release vitamin A from liver so that
health. Macronutrients like carbohydrates, fat it can be used in ocular tissues. It affects the
and proteins build the body and provide it energy cell metabolism through various mechanisms
for all physiological functioning. Micronutrients and maintains normal functioning of the eye. It
that include trace elements and vitamins aid in occurs in high concentrations in ocular tissue,
carrying out various enzymatic processes and particularly in retina and choroid.86 The essentiality
prevent and treat several pathological conditions. of this element has been well established in
Vitamins are the organic compounds, required the retina, choroid, cornea and lens.86 Zinc is
by the body in small amounts whereas trace required for the structure and activity of many
elements are required in very minute quantity. ocular metalloenzymes. Zinc interacts with
The amount of these nutritional agents required taurine and vitamin A in the retina, modifies
for normal physiological functioning is called as plasma membranes in the photoreceptors,
Recommended Dietary Allowance (RDA). regulates the light-rhodopsin reaction within the
Certain eye diseases are the consequences photoreceptors, modulates synaptic transmission
of improper and inadequate quantities of and serves as an antioxidant in both the retinal
nutrients in diet. These diseases can be treated pigment epithelium and retina.86
by supplementation with these nutrients or Deficiency: Zinc deficiency has been suggested
can be prevented by consuming balanced diet. to occur in Parkinson’s disease and may be
This chapter gives a brief account of some specifically related to the vision, olfactory and
of the vitamins and minerals required for the taste loss in these patients.87 It also affects immune
maintenance of healthy eyes. system, vision, fertility, protein synthesis and
other metabolic activities. It is also well known
MINERALS AND TRACE ELEMENTS that zinc deficiency causes functional impairment
in various parts of the eye and dramatically affects
The trace elements are elements required in very the ocular development during early prenatal
minute quantities by the body. These elements period.88 Zinc deficiency is also being linked
act as catalysts in several enzymatic processes. to aging and age-related degenerative diseases,
In minute quantities they are beneficial but can which manifest with an increase in the copper/zinc
cause toxicity in excess amounts. Some of the ratio and systemic oxidative stress in general.89
elements, which affect the normal functioning of Zinc and antioxidants delay the progression
the eye, are described here. of age-related macular degeneration (AMD)
and vision loss, possibly by preventing cellular which being overstimulated, cannot interpret
damage in the retina.90-93 Zn-deficiency induce the signals it receives from the eyes. It focuses
a decrease of myelinated nerve fibers, and it is on the function of one eye while neglecting the
thought that optic neuropathy in patients treated other causing amblyopia.96 High levels of copper
with some drugs such as ethambutol may be a can cause nausea, diarrhea, hepatitis, cirrhosis,
secondary change due to Zn-deficiency following renal dysfunction, sunflower cataract, coma and
drug administration.94 even death (more than 15 mg). Copper levels are
increased due to abnormal metabolism in Wilson’s
Toxicity: Zinc related toxicities have been shown disease.
in human and animal eyes.88 An excessive intake
Sources: Rich sources of copper are beans,
of zinc can cause secondary copper deficiency
mushrooms, barley, tomato juice, potato, cooked
because of the interaction between these two
turnip, beef, chicken, liver, eggs, fish and nuts.97
trace elements. 86
RDA is 2 mg.98
Sources: Zinc rich food are oysters, shell fish, red
meat, poultry and eggs, pork, dairy products, nuts,
Magnesium
fresh fruits, potatoes, beans, canned vegetables,
pumpkin seeds and seafood. Magnesium is an essential mineral, which has
RDA is 11 milligrams of zinc per day for men an important role in human as well as animal
and 8 mg/day for women.95 physiology. Its role in systemic diseases such as
hypertension, heart diseases, and neurological
Copper disorders is known but in ocular tissues the role
is not very clear. Magnesium plays significant
Copper is a naturally occurring element in the role as a cofactor for more than 350 enzymes in
human body and is associated with collagen the body, regulates neuroexcitability and several
production. It is a constituent of several ion channels. Membrane associated ATPase
metalloenzymes such as superoxide dismutase. functions that are crucial in regulating the
Copper along with zinc and vitamin C has an intracellular ionic environment, are magnesium-
important role in oxidative defense mechanism dependent.99 Moreover, the enzymes involved
of the body. Copper actively participates in the in ATP production and hydrolysis are also
formation of hemoglobin in the blood. Copper magnesium-dependent.
with several other antioxidants has been shown to
Deficiency: Magnesium deficiency by interfering
prevent the progression of AMD in clinical trials.
with ATPase functions causes increased
It is stored in the liver and is excreted in bile.
intracellular calcium and sodium and decreases
Deficiency: Copper deficiency is rarely intracellular potassium concentration. Such
seen, however, anemia, poor collagen levels, ionic imbalances in turn alter the other cellular
arthritis, mental deterioration, etc. are some of enzymatic reactions and form the basis of the
the deficiency symptoms of copper. It causes association of magnesium deficiency with
premature graying and discoloration of skin. Zinc ophthalmic diseases such as cataract.100-101 In the
depletes copper, therefore, too much of zinc intake presence of magnesium deficiency, an imbalance
can result in deficiency of copper. between mediators of vasoconstriction and
Toxicity: Copper toxicity affects many systems vasorelaxation may underlie the vasospasm,
in the body. In the nervous system, high levels of which is one of the pathogenic factors in primary
copper produce an abundance of neurotransmitters open angle glaucoma. Furthermore, magnesium
l i k e d o p a m i n e a n d e p i n e p h r i n e . T h e s e deficiency is also a contributing factor in increased
neurotransmitters can cause an overstimulation oxidative stress and stimulation of inducible
of the occipital lobe, the visual processing center, nitric oxide synthase (iNOS) that can further
contribute to the initiation and progression of diseases. It is a mineral and a component of
ocular pathologies such as cataract, glaucoma glutathione peroxidase and thioredoxin, which
and diabetic retinopathy. Researchers have shown recycle glutathione and vitamin C respectively.
its role in the development and maintenance Glutathione is important in various age-related
of corneal structures and cataractogenesis.102 diseases such as cataract and diabetic retinopathy.
Magnesium relaxes smooth muscles, therefore, It increases the immunity and reduces age-related
regulates the outflow of aqueous humor from effects. Selenium helps in the absorption of vitamin
the eye. Its role has been suggested in glaucoma, E and converts it to antioxidants that are vital for
diabetic retinopathy, macular degeneration and ocular health.106 Selenium is used as a cataract
keratoconus. inducing agent in experimental rats.107 However,
Source: Nuts, wheat germ, leafy vegetables. deficient alimentary supply of the essential trace
RDA of magnesium is 320 mg for adult element is also implicated in the development of
women and 420 mg for adult man. cataracts. Several studies have been done on its
relevance to age-related ocular diseases. Selenium
Manganese has a physiological role as selenocysteine residue
in at least 25 distinct selenoenzymes in mammals.
It functions as a component of the antioxidant Flohé reported that clinical evidence for a
enzyme super oxide dismutase (SOD) that prevents protective role of selenium in the development of
the damaging effect of superoxide radicals from cataract, macula degeneration, retinitis pigmentosa
destroying the cellular components.103 Implication or any other ocular disease is not available.108
of altered SOD activity in various ocular diseases
Sources: High levels of selenium is found in egg
have been reported by numerous researchers.
yolk, poultry, sea food, whole grains, wheat bran,
Deficiency: In ocular tissues, a deficiency of brewer’s yeast, and moderate levels are found in
manganese may result in decreased contact onions, garlic, broccoli, etc.
between photoreceptor outer segments and retinal RDA is 55 µg for teens and adults.
pigment epithelium. This is probably related with
the role of manganese in mucopolysaccharide
synthesis, because acid mucopolysaccharides are VITAMINS
present between the photoreceptor outer segments
Vitamins are essential for various physiological
and retinal pigment epithelium.104-105 Another
processes. They can not be synthesized in the
effect of manganese deficiency is a decrease
body or the quantity synthesized is not sufficient
of SOD activity resulting in the accumulation
to meet the requirement, therefore, these are
of free radicals in the cell with consequent
obtained from the diet. Body vitamin requirement
lipid peroxidation in biomembranes.105 Excess
is usually fulfilled by the diet consumed but some
manganese affects the adsorption of iron.
people need vitamin supplements according to
Source: found in nuts spinach and pineapples. their health regimen. There are 13 vitamins that
RDA for males 19 years and older is 2.3 mg of include vitamins A, C, D, E, K, and vitamins B
manganese per day and for females 19 years and (thiamine, riboflavin, niacin, pantothenic acid,
older, 1.8 mg of manganese per day. biotin, vitamin B6, vitamin B12 and folate). Each
vitamin has a special role to play. The low levels
Selenium of any of these may lead to deficiency states.
The benefits and risks of selenium are not fully Vitamins can be water soluble or fat soluble.
understood. Its low levels have been associated Following vitamins are important in maintaining
with number of diseases such as cardiovascular good vision. Their role in preventing ophthalmic
diseases, cataract, cancer and autoimmune diseases is described here.
Fat soluble vitamins which might progress to permanent blindness.114

RDA of vitamin A is 800 micrograms.
Vitamin A
In general, there are two categories of vitamin Lycopene
A, depending on whether the food source is an Lycopene, (Fig. 19.3) a carotenoid, is a potent
animal or a plant. vitamin A obtained from animal antioxidant and scavenges free radicals especially
source is the preformed vitamin A. The body derived from oxygen. It imparts red color to the
absorbs vitamin A in the form of retinol, which is fruits like, tomatoes, strawberries, watermelon,
one of the most active form and gets converted to guava, apricots, etc. Its absorption in the body
retinal and retinoic acid, which are other forms of improves when ingested with good quality oil,
vitamin A. Preformed vitamin A can be obtained such as olive oil.115 Studies have indicated that the
from liver, whole milk, cheese, eggs, fish, fortified absorption of lycopene is more from processed
food products. fruits in comparison to raw fruits and vegetables.
Vitamin A obtained from plant sources is It protects important cellular biomolecules like
called provitamin A, carotenoids. These can be lipids, proteins, DNA, etc. from the effects of
converted into retinol (Fig. 19.1) in the body. oxidative stress, thereby preventing diseases like
Out of the several carotenoids, commonly found cancer, atherosclerosis, AMD and various other
is beta-carotene (Fig. 19.2), alpha carotene and age related diseases. Studies have shown its
beta cryptoxanthin. Among these, beta carotene efficacy in preventing cataract in experimental
can be most easily converted into retinol in the models.116,117
body.109 Lycopene, lutein, and zeaxanthin are In a cross-sectional study, investigating
carotenoids without vitamin A activity but possess relationships between plasma concentrations of
other health promoting properties. Consumption
of carotenoid-rich fruits and vegetables should be
encouraged for their health-promoting benefits.
Some provitamin A carotenoids have
been shown to function as antioxidants in
laboratory studies; however, this role has not
been consistently demonstrated in humans.
Antioxidants protect cells from free radicals, Figure 19.1 Chemical structure of retinol
which are potentially damaging by-products of
oxygen metabolism that may contribute to the
development of some chronic diseases.110-113
Out of several important roles in the body
vitamin A has an important function of the
maintenance of vision. It maintains the healthy
surface lining of the eye forming a barrier to the Figure 19.2 Structure of beta-carotene
bacteria and viruses and preventing infections.
Its deficiency results into dry eyes also known
as xerophthalmia. It is important for the night
vision. Some carotenoids are reported to have
antioxidant activity.
Deficiency of vitamin A may lead to dryness
of the conjunctiva and cornea; Sjogren’s and night
blindness, poor growth and dryness of skin and
hair. Severe deficiency can lead to corneal ulcers Figure 19.3 Structure of lycopene
antioxidant vitamins and carotenoids and cataract becomes cataractous.123 The visible light entering
in elderly men and women, risk of cortical the eye also produces free radicals and focuses
cataract was lowest in those with the highest on the macula lutea of the retina. This area has
plasma concentrations of lycopene.118 highest concentration of photoreceptors and is
Important dietary sources of lycopene include responsible for central vision and high resolution
apricots, strawberries and tomatoes. visual acuity. Lutein and zeazanthin present in this
area act as antioxidants to prevent the area from
Lutein damage due to free radicals and act as filters to
protect the retina from the ill effects of light.124
Lutein is a xanthophyll from the carotenoid
Both lutein and zeazanthin delay age-related
group having antioxidant properties. It is highly
cataract development. In a 12-year-prospective
concentrated in the macular region responsible
study of carotenoid intakes and risk of cataract
for central vision and high visual acuity. Lutein
protects the macula against photo-oxidative extraction in women, those with the highest intake
damage by functioning as antioxidant and/or of lutein and zeazanthin had a 22% reduced risk
optical filter.119,120 It is found in dark green leafy of cataract extraction when other potential risk
vegetables such as spinach, broccoli, fruits, factors were controlled. These researchers also
corn, egg yolk, etc. Lutein’s role in reducing found that increasing intake of spinach and kale,
the risk of AMD has been reported by several foods rich in both lutein and zeazanthin, was
researchers. 110-113 It has also been shown that associated with a moderate decrease in the risk of
people consuming high quantities of lutein have cataract.125 Results from another large prospective
25 to 50% less risk for having cataract than the study, with eight years of follow-up, showed that
people consuming lesser amounts of lutein. No men with the highest lutein and zeazanthin intake
RDA has been specified for lutein, however, a had a 19% lower risk of cataract than those with
minimum of 6–10 mg of lutein per day provides the lowest intake.126
necessary health benefit.111
Vitamin D
Zeazanthin Vitamin D is synthesized in the body upon
An isomer of lutein, zeazanthin is also found in exposure to UV light. It increases the absorption
the retina of eye. It predominates in the central of calcium and phosphate and maintains healthy
macula. High dietary intake of zeazanthin rich immune system. The common naturally occurring
food is associated with lower incidence of form of vitamin D is cholecalciferol. Sunlight
AMD.121,122 is the best source of vitamin D. Codliver oil,
Several carotenoids are present in the human eggs and milk are some of the other sources of
body as a result of consumption of food or dietary vitamin D.
supplements. These are not synthesized by the An ophthalmic composition containing
human body. Among all the carotenoids present, ergocalciferol or cholecalciferol, i.e. a vitamin
lutein and its isomer zeazanthin are present in D, has been shown to be effective in normalizing
the eye where the light is focused by the lens, the transparency and refraction of the eye by
the macula lutea. Cornea and the lens of the eye restoring the disturbed metabolism in eye tissue.
are the two structures, which protect the eye By protecting the eyes against UV radiation,
from the ill effects of the ultraviolet light acting the ophthalmic composition of vitamin D has
as a filter to remove the UV light. The light thus been shown to prevent corneal diseases such as
filtered falls on the retina. The lens due to the photokeratitis, corneal ulceration and corneal
exposure to light gradually loses its transparency dystrophy, which may be caused by UV radiation.
because of the changes in the protein structure and Moreover, it reduces opacity of the lenticular
capsule after cataract surgery.127 An ophthalmic Thiamine (B1 ): It is a water soluble B complex
composition of vitamin D, active vitamin D, vitamin, earlier known as aneurine. It is
and active vitamin D analogues has been shown essential for growth and development (Fig.
to be effective for prophylaxis and treatment of 19.5). Vitamin B 1 imparts anti-stress action
keratoconjunctivitis sicca.128 like other B vitamins. It helps in the synthesis
Animal experiments have shown that of a neurotransmitter, acetylcholine, which is
vitamin D plays an important role in treating an essential neurotransmitter. Any abnormality
retinoblastoma.129 in acetylcholine metabolism compromises the
Recommended Daily Allowance (RDA) for formation of new memories and the ability of cells
vitamin D is 5 micrograms per day (200 IU). to send messages to each other is lost. Thiamine
is involved in several body functions such as
Vitamin E nervous system and muscle functioning; flow
of electrolytes in and out of nerve and muscle
Vitamin E (Fig. 19.4) is a fat soluble vitamin cells; multiple enzyme processes; carbohydrate
which occurs in several chemical forms such as metabolism and production of hydrochloric
a-tocopherol, b-tocopherol, g-tocopherol and acid in the stomach.132 It preserves the muscle
d-tocopherol. Alpha tocopherol is predominantly tone along the digestive tract and maintains
present in retina and plasma130,131 and is the most the general health of eye, skin, hair and mouth.
potent free radical scavenger. It protects against Researchers have shown its involvement in heart
various ocular diseases such as glaucoma, cataract failure, Alzheimer’s and eye diseases such as
and macular degeneration. It also inhibits the toxic cataract.133-135
effects of fat oxidation on the retina. It is found in lean meat, unpolished grains,
Sources of vitamin E are wheat germ oil, cereals, dried beans, bran, soyabeans, wheat
margarine, egg yolk, nuts, spinach, etc. Daily germ etc. Deficiency causes Beri-beri, Wernicke’s
requirement of vitamin E is 10 mg.
encephalopathy and Wernicke-Korsakoff
syndrome. RDA is 0.3 to 1.6 mg/day.
Water Soluble Vitamins
Riboflavin (B2 ): Riboflavin or vitamin B2 is the
Vitamins B central component of cofactors FAD and flavin
Group of eight distinct vitamins including mononucleotide (FMN) or Flavin 5 phosphate
vitamins B 1 (Thiamine), B 2 (Riboflavin), B 3 required by all flavoproteins (Fig. 19.6). It has
(Niacin or niacinamide), B 5 (Pantothenic an important role in energy production from
acid) , B 6 (Pyridoxine) , B 7 (Biotin) , B 9 (Folic fat, carbohydrate and protein metabolism and
acid) , B 12 (Various cobalamins, commonly activation of vitamin B6 and folic acid. It is found
cyanocobalamins) is called as vitamin B complex. in milk, liver, kidneys, legumes, leafy vegetables,
Figure 19.4 Structure of vitamin E Figure 19.5 Structure of thiamine

yeast, tomatoes, and nuts. The food containing Both form the coenzymes nicotinamide adenine
riboflavin should not be kept in light as it gets dinucleotide (NAD) and nicotinamide adenine
destroyed by exposure to light. It is water soluble dinucleotide phosphate (NADP), which are
and excess quantity is excreted in urine. Excess used for a number of biological oxidation
riboflavin excreted in the urine gives the typical reduction reactions.139 Like all other B vitamins,
yellow color to the urine. Sore throat, bloodshot it plays a role in lowering the blood pressure
eyes, abnormal skin sensitivity, itching and and blood cholesterol. It also dilates the blood
burning of the eyes, cracked lips and corners vessels. Because of this property it might help
of mouth, swelling of mucous membranes and in improving the blood flow to the optic nerve.
skin are some of the symptoms of deficiency of It has been shown to produce retinal arterial
riboflavin. Its use in the prevention and treatment vasodilation.140
of cataracts and glaucoma has been described.136 Yeast, fish, sunflower, legumes, liver, kidney,
Corneal vascularization, corneal opacity and poultry and lean meat are some of the best dietary
cataracts have been described in animals fed diets sources of vitamin B3. The deficiency of B3 causes
low in riboflavin. However, the importance of pellagra, which is characterized by cracked scaly
riboflavin deficiency in the etiology of cataracts skin, dementia and diarrhea.
in elderly humans is not fully understood. RDA is 16 mg (RDA) for males 19 years and
Riboflavin deficiency may be associated with older and 14 mg for females 19 years and older.
night blindness in some communities and that Pantothenic acid (Vitamin B5 ): This vitamin aids
improving riboflavin status might enhance the in the metabolism of fat, protein and carbohydrate
improvement in night blindness evoked by and production of neurotransmitters, hormones
vitamin A.137 and antibodies.
RDA for riboflavin is 1.7 mg/day for an adult Deficiency leads to neuromuscular degener
man and 1.3 mg/day for an adult woman.138 ation and adrenocortical insufficiency.
Niacin or Niacinamide (Vitamin B3 ): Niacin Mostly found in meat, vegetables, cereal
(Fig. 19.7) refers to both nicotinic acid and its grains, legumes, eggs, and milk. RDA is 6 mg.
amide derivative, nicotinamide (niacinamide). Pyridoxine (Vitamin B ): Pyridoxin (Fig. 19.8)
6
is one of the B vitamins that helps in maintaining
the healthy nerves and muscles and the production
of DNA and RNA. It activates several enzymes,
helps in absorption of vitamin B 12, fats and
proteins, boosts immune functions and antibody
production. It may be useful for people with
eye infections, bladder infections, prevention of
cancer, AMD and kidney stones.
Pyridoxine deficiency is characterized by the
development of a greasy and scaling dermatitis
involving the skin around the eyes, ears, nose
Figure 19.6 Structure of riboflavin Figure 19.7 Structure of niacin

B6 and B12 had lower risk of AMD compared to
other women.142 Green vegetables, fruits, milk,
eggs, liver, kidney, yeast are good sources of folic
acid. Deficiency causes megaloblastic anemia and
teratogenic effects.
Vitamin C (L-ascorbic acid or

L-ascorbate)
Figure 19.8 Structure of pyridoxin Vitamin C (Fig.19.9) is an essential nutrient
for humans and animals. It is an antioxidant
and protects against oxidative stress. 143 It is
and the mouth, and the areas of the body that are
synthesized by most of the animals in sufficient
frequently rubbed together, like the skin around
amount but not in humans.
the inner thighs. In rare cases, the deficiency of
It acts as a cofactor in a number of enzymatic
vitamin B6 can induce impaired immunity and
reactions. Its antioxidant property helps in
retardation of the immune response, skin lesions
reducing the effect of free radicals in the eye.
and mental confusion.141
Studies have indicated that the vitamin C intake
Rich sources of B6 are poultry, fish, whole
has resulted in lowering of intraocular pressure in
grains, soybeans, bananas, cabbage, spinach, peas,
patients with elevated pressure.144 Higher intake
carrots, avocados, etc.; 10–25 mg per person a day
of vitamin C, alone or in combination with other
is recommended.
antioxidants, had a protective association with the
Cyanocobalamin or hydroxocobalamin (Vitamin long-term (10 years) incidence of nuclear cataract
B12 ): This vitamin is not synthesized in human in one of the population-based cohort study.
body but can be obtained from yeast, liver, These findings support the hypothesis that diet
meat, fish, and eggs. The vitamin is important in and supplement intakes of vitamin C and other
production of red blood cells, lipids and amino antioxidants may exert age-related ocular benefits,
acids. as well as beneficial effects on aging itself.145
The deficiency is characterized by pale skin, However, it has been reported that antioxidant
shortness of breath, headache, dizziness, cold supplementation with β carotene, vitamins C
palms and feet. Pernicious anemia is a serious and E did not affect cataract progression in a
complication of reduced production of RBCs. population with a high prevalence of cataract
Deficiency can also lead to permanent nerve whose diet is generally deficient in antioxidants.146
damage. Daily requirement is 2–3 µg/day.
Folic acid (Vitamin B9 ): Folic acid is another
water-soluble vitamin B which is useful in
maintaining overall health. Children and adults
require folic acid for healthy red blood cells. Its
deficiency may result in fetal abnormalities.
Absence of folic acid and a handful of other
micronutrients causes preventable deformities
and diseases, especially in fetal development. It is
useful in Alzheimer’s disease, depression, anemia,
and certain types of cancer. Studies indicated that
women on supplementation of folic acid with Figure 19.9 Structure of vitamin C
High doses of vitamin C have also been reported Low levels of taurine are related with macular
to be associated with higher risk of age related degeneration and glaucoma. Animal products
cataracts in women.147 Vitamin C as eyewash is such as meat, eggs, and fish are good source of
used for quick healing of conjunctivitis. It also taurine.
alleviates dry eyes. In some countries (Russia, Armenia, Georgia,
Plants are the main source of vitamin C for Ukraine, Kazakhstan and Belarus) taurine 4%
humans. Rich sources of vitamin C are broccoli, solution (Taufon Eye Drops) is prescribed to
green cabbage, kale, cauliflower, tomatoes, kiwi adults with hereditary tapetoretinal degeneration,
fruit, oranges, lemons, papayas. corneal dystrophy, senile, diabetic and traumatic
The RDA for vitamin C is 60 mg for both men cataract. Taufon reduces intraocular pressure in
and women. patients with glaucoma.152,153
AMINO ACIDS SUMMARY

Not only vitamins and minerals affect the normal Nutritional agents have a remarkable role in
vision, but some amino acids like cysteine and maintaining the clarity of vision and this has
taurine are reported to have a significant role in been proved by a number of studies. The diet
maintaining the normal vision and repairing the consumed should contain green leafy vegetables,
damaged ocular tissues. fruits, nuts, milk, milk products, meat, egg, etc. It
Cysteine is an important amino acid that should be rich in antioxidants, vitamins, minerals,
helps to maintain a healthy retina. It helps in and omega-3-fatty acids and deficient in saturated
increasing the production of glutathione. It has an fat. This can ameliorate the age related changes
important role in macular degeneration, glaucoma occurring in eye and provide protection from
and cataract.148 It can be obtained from eggs. the harmful effects of chemicals, radiations and
Recommended dose is 500–1000 mg daily as various pathological conditions.
N-acetyl cysteine.
Taurine is a free amino acid that acts as an
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ChapteR 20
Gene Delivery and Disease
Modulation in the Eye
OVERVIEW including therapeutic molecules. Thus ocular

drug delivery has been a major challenge plaguing
Blindness resulting from trauma, injury or disease pharmaceutical scientists. The most common and
is a notable health care concern worldwide.1 preferred method employed is topical treatment
Limitations of currently available management (Fig. 20.1) (e.g. eye drops, and ointments), because
options for prevalent ocular impairments such of low cost and ease of treatment application.10,
as glaucoma, corneal damage and disease, and 11
Unfortunately, low bioavailability results from
age-related macular degeneration, etc. result in reflex blinking, lacrimation, and nasolacrimal
treatments that are ineffective, costly to patients drainage that cause the loss of a major fraction
and healthcare systems, and toxic to application of the topically applied treatment. Additionally
sites due to various adverse effects.2, 3 Therefore, the corneal epithelium is a restrictive barrier
much work has been done to develop effective, compromising drug permeability into target
affordable, and practical treatments for patients. ocular tissues. As a result, less than 5% of the
Gene therapy is a promising therapeutic approach applied treatment reaches intraocular regions.12
for many ocular pathologies. The concept of using This approach may be useful in treating disorders
this strategy to alleviate blindness in humans was in the anterior segment of the eye, however in
supported by the first successful ocular gene therapy order to maintain therapeutic concentrations,
studies in 2008 in which vision was restored to frequent application is required which may cause
patients with Leber’s congenital amaurosis, a adverse effects.13, 14
congenital disease characterized by severe retinal Delivery methods used to bypass the protective
dystrophy.4-8 With gene therapy, specific cell types barriers of the ocular anterior surface include
can be targeted and converted into pharmacological systemic and microinjection administration (Fig.
factories able to continuously generate therapeutic 20.1). Systemic administration is beneficial in
agents.9 Consequently, with a single dose, gene the management of diseases involving posterior
therapy has the capability to correct the underlying eye regions. However, tight junctions of the
disease mechanisms, contrasting conventional blood retinal barrier may restrict therapeutic
molecule entry into the retina. Like with topical
methods that mask symptoms.9
applications, this limitation results in frequent
administration and potential toxic side effects.15, 16
CONVENTIONAL OCULAR DELIVERY Another drawback is that only a small fraction
METHODS AND BARRIERS (1–2%) of systemically dispensed therapeutic
agents will reach the vitreous.15 This issue can
The unique protective structures of the eye be resolved by direct injections into the vitreous.
prevent the entrance of foreign molecules, Intravitreal injections supply the retina and the
Gene Delivery and Disease Modulation in the Eye 287
Topical Application Intraocular Injection Systemic Injection
Advantages Advantages Advantages

•• Low cost Periocular and Bypasses anterior
•• Ease of application Intravitreal barriers
•• Treatment: •• Regions may be Supply therapeutic
exposure to less resistant to agent to posterior eye
anterior tissue foreign molecules regions
layers •• High concentration
accumulate in Limitations
Limitations vitreous and retina Retinal tight junctions
Low bioavailability: may restrict entry into
•• Reflex blinking Limitations retina
•• Lacrimation and Periocular Results in frequent
nasolacrimal •• Cataract formation, administration which
drainage increased IOP, may lead to toxic side
•• Corneal epithelium strabismus, effects
barrier hyphema, corneal Only small fraction
•• Unable to penetrate decompensation reaches vitreous and
into posterior eye Intravitreal other anterior eye
regions •• Risk of retinal segments
•• Causes loss of large detachment,
volume of applied endophthalmitis
treatment, requiring and intravitreal
frequent application hemorrhage with
which may lead repeated injections
to adverse side
effects
Figure 20.1 Advantages and limitations of conventional ocular therapeutic delivery methods
vitreous with adequate concentrations of the TYPES OF GENE THERAPY VECTORS

treatment.17 However, although this technique
bypasses physical barriers, repeated injections There are two major types of gene therapy
of treatments with shorter half-lives increase the delivery vectors, viral (Table 20.1) and non-
risk of retinal detachment, endophthalmitis, and viral. An ideal vector is able to target dividing
intravitreal hemorrhage.11, 18 Periocular injections, and non-dividing cells, deliver beneficial levels
injections into areas neighboring the eye, have of therapeutic genes at desired ocular tissue or
also been considered an efficient delivery location, and does not induce an immunological
method for administering therapeutic agents to response or cause toxic side effects.9
posterior segments of the eye. Periocular is a
broad term that indicates peribulbar, retrobulbar, Viral Vectors
subconjunctival, and posterior juxtascleral
delivery routes. 10 The sclera, for example, is Adenovirus (AV) Vectors
less resistant to foreign molecule permeability AV is a virus with double stranded DNA and
due to its fibrous tissue make up. Therapeutic over 50 known human serotypes. Serotypes 2
molecules applied near this region lead to high and 5 are most commonly used in gene therapy.21
concentrations within the vitreous and retina.19 AVs deliver foreign genes into host cells via
Complications associated with periocular receptor-mediated endocytosis. To gain entry into
injections include cataract formation, increased the cell, the AV binds to a cell surface receptor
intraocular pressure, strabismus, hyphema, and (coxsackie-adenovirus receptor), and assembles a
corneal decompensation.20 clathrin-coated pit. Upon entry, the viral genome
288 Textbook on Ocular Pharmacology and Therapeutics
is released and transported into the nucleus where and overcome this challenge. 25,30 However,
it is expressed episomally.3 AV vectors offer in addition to being associated with a severe
many advantages for gene therapy application immune response and subsequent inflammation,
including their ability to transduce dividing and gene expression of AV vectors has been noted
non-dividing cells, carry genes ~30 kb, naturally to be transient. Previous studies demonstrated
infect human tissue, and also their inability to that the short-term transgene expression requires
integrate into the host genome. AV vectors have repeated dose administrations, and consequently
been shown to successfully deliver genes in repeated treatments were toxic.22 In summary,
vivo and in vitro to specific cornea cell types in AV vectors are promising ocular gene therapy
rodents and sheep, and ex vivo in humans.3, 22-29 tool (Table 20.1), however, additional research
High immunogenicity is one major limitation is needed to improve their safety.
to the use of AV-mediated therapeutic delivery.
Also patients with previous exposure to wild- Adeno-associated Virus (AAV) Vectors
type AV generate a strong immune response,
which rapidly targets and kills transfected cells. AAV belongs to the parvovirus family and
To improve the suitability of AV vector usage in has been demonstrated to be an efficient gene
gene therapy, efforts have been made to address therapy vector. Of the 110 known serotypes, only
Table 20.1 Characteristics of viral vectors used in ocular gene therapy

Adenovirus Adeno-associated Retrovirus Lentivirus
virus
Vector size (nm) 70–90 18–26 80–130 80–130
Viral genome 38–39 4–7 3–9 3–9
size (kb)
Genome type dsDNA ssDNA ssRNA ssRNA
Payload size ~7.5 ~1.8 ~8 ~8
capacity (kb)
Tropism Mitotic cells Mitotic and post- Mitotic cells Mitotic and post-
mitotic cells mitotic cells
Integration into No No Yes No, Yes if impaired
host genome
Transduction Low-high Mid-high Mid-high High
efficiency
Transgene Transient (days- Potentially extended Extended (months- Extended (months-
expression weeks) (months-years) years) years)
duration
Immunogenicity High Low-mid Mid-high Mid-high
level
Pros High titer, able Very effective for Very effective, Very effective for all
to infect most all cell types, stable allows sustained cell types, allows
cell types, non- transduction, site- gene expression sustained gene
mutagenic specific integration expression
Cons Immunogenic, Small size of insert, Requires dividing Immunogenic, HIV
common virus low immunogenicity, cells, low titer, origin, random
in humans that potential for HSV oncogenic, random integration potential
reduces potency or adenovirus integration
contamination
serotypes 1-10 have been tested for gene therapy. rabbit model in vivo.32 After creating a lamellar
This small virus has an icosahedral capsid, and flap using a microkeratome, this vector was
a single-stranded DNA genome spanning 4.7 kb. applied topically onto the stromal bed and
The AAV genome has two open reading frames caused considerable gene transfer, supporting
(ORFs) encoding for Rep and Cap. These ORFs the hypothesis that successful keratocyte gene
are found between inverted terminal repeats that delivery is dependent on a breached epithelial
are comprised of 145 bases and located at the 5’ barrier. Because AAV2 is naturally found in
and 3’ ends. The Cap genes encode for capsid humans, AAV2 may induce a humoral immune
proteins VP1, VP2, and VP3. The Rep ORF response or inflammation, and consequently
encodes four proteins: Rep40, Rep52, Rep68, diminish the AAV2 potency. To circumvent this
and Rep78. Rep68 and Rep78 are responsible for problem, hybrid AAV vectors were developed
replication and translation of the AAV genome, using the genome from AAV2, and the capsid
while Rep40 and Rep52 orchestrate the packaging from different serotypes. These hybrids were
of the genome within the capsid. capable of efficiently transducing several ocular
Once assembled, the virus binds to the tissues in several species.33-38 Significant tissue-
appropriate cell surface receptor. This serotype- specific delivery of AAV2/5 to the stroma of
specific event is determined by capsid sequence, rabbit and rodent cornea was observed, and
and is responsible for tissue trophism variability transgene expression lasted up to 12 months.25, 38
between serotypes. After binding of the viral Serotype AAV2/6, 2/8, and 2/9 hybrid vectors
capsid to its primary receptor, the viral particle have also shown promising results in the transfer
enters the cell via receptor-mediated endocytosis of genes to human corneal fibroblasts in vitro,
and through endosomal lysis the genome is human corneas ex vivo, and in rodent corneas
released into the cytoplasm. The genome then in vivo.37-39
anneals to a complementary DNA strand provided The delayed initial appearance of transgene
either by host machinery or another infecting expression was another limitation in the
virus. After reaching the nucleus, the AAV development of efficient AAV vectors. The
genome either remains episomal, or is integrated delayed initial expression occurs due to the
into chromosome 19 of the host genome by complementary DNA annealing step where
Rep68 and 78. Translation of the viral genome is the single-stranded viral genome is converted
conducted by host cell machinery. 3 into double-stranded DNA. To resolve this
The first recombinant AAV (rAAV) vectors problem, double-stranded self-complementary
were generated by replacing the two ORFs with AAV (scAAV) vectors were developed. Hairpin-
a gene of interest. This process required both E1 forming terminal repeat segments are necessary
expressing HEK293 cells that contained a helper for AAV replication and packaging, and the
plasmid expressing Rep and Cap, and E1 deficient encouragement of the formation of dimeric
AV. Initially, helper virus contamination impeded inverted repeat genomes is possible. If small
vector production, however, this problem was enough, dimers can be packaged into the viral
resolved in the second-generation rAAV vectors, envelope, and upon release into the host cell,
by replacing the E1 deficient AV with an AV- they can spontaneously self-anneal. This process
helper-plasmid expressing E4 and E2A. To results in double-stranded DNA that is available
eliminate the need for dual transduction, further for quicker gene expression.40-42
modifications were instituted, including the Although many of the limitations encountered
combination of the AAV-helper and AV-helper with initial AAV vectors have been resolved, there
genes into one plasmid.31 are several inherent drawbacks of these vectors,
AAV2 was the first serotype to demonstrate which have been proven challenging to overcome.
significant gene delivery in the cornea using a Because of their small size, therapeutic genes
greater than 1.8 kb are difficult to package. Also retroviral vectors are also highly immunogenic.9
generating high viral titers is time consuming Therefore, while there are many advantageous
and technically demanding, and immunological characteristics of viral vector usage for gene
concerns exist in cases where humans have been delivery, major safety and toxicity concerns
previously exposed to serotypes 1–6. have been noted. 9
Retrovirus Vectors Lentivirus Vectors

Retroviruses are composed of two identical, linear Lentiviruses, like the commonly used HIV1
single-stranded RNAs located in a cylindrical vector, are a type of retrovirus that can be
nuclear core. With a genome size of ~7–11 kb, modified for gene therapy use. Similar to other
retroviruses consist of three subfamilies including retroviruses, lentiviruses are enveloped viruses
oncovirinae, lentivirinae and spumavirinae, containing a single-stranded RNA genome within
with oncoretroviruses being the first viruses its cylindrical core. Approximately100 nm in
used in gene therapy. Retroviruses contain three size, each particle has two copies of its genome
vital genes:gag, pol, and env. Gag encodes containing characteristic retroviral genes (e.g. p7,
for structural proteins of the virus, pol for gag, pol, and env). Encoding for several additional
reverse transcriptase/intergrase, and env for long gene products, they also have six ORFs.47-49 The
terminal repeat (LTR) flanked viral envelope mode of gene delivery is essentially the same
glycoproteins. To deliver foreign DNA to a cell, as other retroviruses, except that the lentiviral
viral envelope proteins bind host cell surface genome is expressed episomally.3
receptors.3 Prior to membrane fusion, the viral HIV-derived vectors used in gene therapy
core enters the cell where the viral genome is undergo several modification steps in order to
released. Reverse transcriptase converts the viral develop a vector without infectious and replication
genome into double stranded proviral DNA. capabilities. For example, removal of integration
The genome is then translocated to the nucleus capabilities has been achieved by the replacement
and integrated into the host genome, via viral of LTRs with self-inactivating LTR hybrids. The
intergrase, where LTR-associated transcription subsequent construct has a small fraction of the
factors in the viral genome initiate transcription original viral genome50, and reduced potential of
of new viral particles.3 integrating into the host genome. Lentiviral vectors
Retroviral vectors are very valuable tools are capable of penetrating intact nuclear membranes
for in vitro studies. They are commonly used to allowing them to transduce non-dividing cells.
immortalize ocular cells that characteristically Also, compared to other retroviral vectors, they
do not grow in culture; including corneal appear less toxic to the host genome. Lentiviruses
epithelial and endothelial cells and donor corneas have been demonstrated to target and efficiently
from normal and Fuchs’ dystrophy patients.43-46 transduce many corneal cell types (e.g. epithelium,
Retroviral vectors can hold large therapeutic endothelium and keratocytes) in vitro, in vivo and
genes (~8 kb) and are capable of providing ex vivo with high transgene expression.51-55 These
long-term expression of therapeutic genes integration-deficient vectors appear promising for
in dividing cells. 9 However, because random ocular gene therapy over other retroviral systems,
integration into the host genome increases however, the risk of integration still remains a major
the risk of insertional mutagenesis, retroviral translational obstacle.49
vectors may be oncogenic and, therefore, Development of nonviral gene delivery
limit their application in human therapies. 9 vectors was initiated in the early 1970’s after
They are also not capable of transducing Graham and colleagues utilized chemical
non-dividing cells, and similar to AV vectors, methods to successfully transform cells.56 This
early success led to the development of many toxic.61, 62 It has also been shown to transiently
other nonviral vectors including plasmids, increase corneal permeability, enhance ocular
lipids, and nanoparticles. Nanoparticles are bioavailability, and penetrate conjunctival
promising tools in ophthalmology because they epithelia cells via paracellular and transcellular
have low immunogenicity, high gene-carrying pathways. 62-64 Due to its electrostatic interaction
capacity, and an affordable cost of commercial with negative charges in the mucus layer,
production. 57 One of the biggest limitations polycationic chitosan has been identified as
of non-viral vectors has been low transfection a promising ophthalmic treatment vector. 62
efficacy and short gene expression duration.58 Additionally in rodent keratocytes, successful
Working at the subcellular level, the ultimate marker gene expression was reported following
goal of nanomedicine is to achieve therapeutic intrastromal injection of chitosan nanoparticles.65
benefit through the comprehensive defense, Albumin facilitates its role as a vector for drugs
repair, and control of biological systems using and oligonucleotides because of its highly charged
nanostructures.59 amino acid composition.66 Albumin nanoparticles
have been documented to effectively deliver a
Nonviral vectors: Nanoparticles gene encoding a soluble vascular endothelium
growth factor into the cornea, and to decrease
Nanoparticles are particles ranging between 1–100 neovascularization without major adverse
nm in size. Because living cells generally have a effects.67 Polymers and copolymers like PLA
diameter between 10,000 nm and 20,000 nm, the (poly lactic acid) and (poly D,L-lactide-co-
small magnitude of nanoparticles gives them the glycolide) PLGA, are also biocompatible and
ability to access intracellular compartments with biodegradable resulting in their common use
little impact on cell membranes.38 The smallness as building blocks for nanocarriers. PLGA has
also provides a large surface area to volume ratio; shown some capability to transport genetic
therefore, a myriad of ligands (e.g. antibodies, material to rabbit conjunctival epithelium. 68
peptides, DNA, and probes) can be incorporated
Gold nanoparticles (GNPs) are appealing
giving rise to a multitude of therapeutic treatment
gene therapy vectors because they have minimal
options. 30 Nanoparticles can also be tagged
toxicity, can efficiently condense DNA, and are
with molecular sensors and fluorescent markers
easy to synthesize.69 It has also been demonstrated
to enhance uptake into specific target cells,
that GNPs successfully transported marker
and to track in vivo. 9 Additionally, the high
genes in various mammalian cells.70-74 Recently
specificity and small size may reduce the amount
our group was one of the first to investigate
of therapeutic agent administered and side effects.
There are three major categories of the applications of hybrid GNPs as therapeutic
nanoparticles that have been investigated delivery vectors in the cornea. A study was
for therapeutic delivery into ocular tissue conducted to assess the safety and efficiency of
including polymeric, metallic, and hybrid metal- PEI2-GNPs (2 kDa PEI conjugated to GNPs) in
polymeric nanoparticles. Polymeric particles vivo using a rabbit model.75 With and without the
are composed of organic polymers such as removal of corneal epithelium, PEI2-GNPs were
polyethylene glycol (PEG), chitosan, albumin applied topically using a cloning cylinder (to
and polyethyleneimine (PEI).10 PEG is the most enhance target tissue delivery specificity). Corneal
commonly studied polymer in ocular application tissue exhibited marked PEI2-GNP uptake with
due to low immunogenicity.60 It has also been slow clearance over time. Additionally, GNPs
used to successfully deliver plasmids to the were detected in the extracellular matrix and
retina, lens, cornea, and trabecular meshwork keratocytes, and slit-lamp biomicroscopy revealed
invivo. 58 Chitosan is a deacetylated chitin, no signs of inflammation or edema.75 The results
which is biocompatible, biodegradable and non- from this study indicated that PEI2-GNPs are
attractive candidate vectors for safe and effective of gene therapy vectors and genes tested for
gene therapy in corneal tissue.75 anterior eye disorders is presented in table 20.2.
Corneal Graft Rejection

GENE THERAPY APPLICATIONS IN
OPHTHALMOLOGY Keratoplasty is a commonly used treatment for
various corneal pathologies. While this procedure
is generally effective, allograft immunological
Anterior Eye
rejection and consequent failure are major
Applications of gene therapy have been concerns.76 Attempts to enhance graft survival by
investigated in diseases of anterior segment, gene therapy have focused on modulating wound
particularly those affecting the cornea. A summary healing, angiogenesis, apoptosis, and cellular
Table 20.2 Gene therapy vectors and genes tested for anterior eye disorders
Corneal Graft Corneal Wound Corneal Alkali Conjunctiva and
Rejection Healing Burns lacrimal glad
dysfunctions
Adenovirus vector Adenovirus vector Adenovirus vector Adenovirus vector
•• CTLA-4 •• Soluble Type II •• SMAD 7 •• IL 10
•• CE2F2 transforming growth •• BMP 7 •• p38 activated protein
Lentivirus vector factor (TGFb) •• Peroxisome kinase
•• bcl-xl receptor proliferator-activated •• Smad 9
•• bcl-2 Adeno-associated virus receptor (PPAR) λ •• (PPAR) λ
•• p35 vector Gold nanoparticle
•• IDO •• Decorin •• BMP 7
Plasmid
•• Tissue plasminogen
activator
Corneal neovascularization: Corneal scarring: Herpes simplex virus
Plasmid Retrovirus vector type-1
•• Kringle 5 plasminogen •• Herpes simplex virus Plasmid
•• IL12 (HSV) thymidine •• HSV-1 glycoprotein’s
•• IL10 kinase (G, D, and gB1)
•• Vascular endothelial growth factor receptor FLT-1 •• Dominant-negative •• Interferon
•• FLT24K cyclin G1 •• TNFa
•• FLT23K Nanoparticle •• IL2
Albumin-derived nanoparticle •• Bone morphogenic •• IL4
•• FLT23K protein 7 •• IL10
Adenovirus vector •• Soluble type II
•• Vascular endothelial growth factor receptor FLT-1 transforming growth
factor (TGFb)
Adeno-associated virus vector receptor
•• Vascular endothelial growth factor receptor FLT-1
•• Angiostatin Adeno-associated virus
•• Pigment epithelium-derived factor (PEDF) vector
•• Decorin •• SMAD 7
•• Decorin
Lentivirus vector
•• Endostatin/kringle-5 domain of plasminogen Corneal neuropathy and epithelopathy, and
fusion protein dystrophies
Adenovirus vector
•• cmet
•• b-glucuronidase
transport.76 Lentiviral transport of anti-apoptotic release and hyperactivity following injury
genes (bcl-xL, bcl-2, surviving, and p35) was has been shown to be involved in profibrotic
shown to extend graft survival in a rodent model.77 myofibroblast generation. Because TGFβ can
Similarly enhanced endothelial cell survival was transmit signals through the Smad pathway, it
observed after delivery of anti-apoptotic genes has been demonstrated that modulating Smad
into human corneas and primary endothelial cells protein expression (Smad 2, 3, and 7) may
using lentiviral vectors.78 Adenoviral vectors potentially inhibit corneal scarring.82 Additionally,
have also been shown to extend endothelial inhibition of the fibrotic function of TGFβ
cell survival and amplify cell counts in human has been accomplished utilizing a natural
and rabbit corneas.79 McAlister and colleagues inhibitor of TGFβ, decorin (a small leucine-rich
demonstrated that the delivery of transcription proteoglycan). Decorin significantly inhibited
factor E2F2 ex vivo protected endothelial cells myofibroblast induction when delivered into
via modulation of cell cycle phases.79 human corneal fibroblasts, without affecting cell
Modulation of T cell activation in and around viability.83, 84 Furthermore, tissue specific delivery
the graft site has also been tested in efforts of decorin significantly decreased corneal fibrosis
to decrease the odds of immune rejection. when administered via AAV2/5 vector in vivo
without apparent side effects.85
Encouraging immune tolerance, indoleamine
2, 3-dioxygenase (IDO) is believed to prevent
Corneal Neovascularization
activated T cell division by halting T cells in
the G1 phase. Lentivirus-mediated delivery of Corneal neovascularization (CNV) results in
IDO significantly prolonged graft survival in increased risk of anti-inflammatory response,
rodent full-thickness corneal grafts and corneal loss of corneal transparency and blindness.
endothelium. 80 These studies emphasize the Targeting the vascular endothelial growth
promising potentials of gene therapy applications factor (VEGF) pathway may be a promising
in enhancing corneal allograft survival. approach to treating this disorder. Inhibition
of injury-induced neovascularization was seen
Corneal Scarring and Wound Healing after albumin-derived nanoparticles were used
Injury, infection or trauma of the cornea often to deliver constructs containing Flt32K, a VEGF
results in corneal opacification and vision loss. This receptor gene, to keratocytes.67 Similarly Flt-1
opacification is believed to result from a fibrotic and Flk-1 also inhibited CNV in rodent eyes when
response, regulated by numerous chemokines delivered via adenoviral vectors.86, 87 Inhibition of
and cytokines. In a rabbit fibrosis model, corneal CNV was also demonstrated by the coupling of
retroviral-mediated delivery of dominant-negative Flt23K or Flt24K peptides with an endoplasmic
mutant cyclin G1 was used to block cyclins reticulum-retaining peptide, which led to the
and cyclin-dependent kinases involved in the intracellular sequestering of VEGF following
control of cell division.81 Corneas expressing the intrastromal injection into rodent eyes.88, 89 Genes
construct displayed decrease corneal haze, likely involved in regulating vascular endothelial cell
because of activated keratocytes apoptosis. 81 adhesion, proliferation, migration, and apoptosis
An alternative tactic to modulate fibrosis would have also shown reduction of CNV in rodents.90-92
be to limit keratocyte proliferation. In a laser- Additionally, epithelium derived factor, CD26,
induced corneal haze model, haze was reduced by GA-binding protein, IL18, and decorin are other
retroviral delivery of the thymidine kinase gene genes showing promise for CNV treatment.
following keratectomy.81 Decorin, for example, significantly reduced CNV
Another cytokine believed to play a large in rabbit eyes in vivo when delivered with an
role in the fibrotic cascade is transforming AAV5 vector, and showed no apparent adverse
growth factor beta (TGFβ). TGFβ’s increased side effects.93
Corneal Dystrophies mediated Smad7 expression antagonized corneal

scarring. Bone morphogenic protein-7 (BMP7)
Patients suffering from various corneal dystrophies also demonstrated antagonistic effects against
may benefit from gene therapy treatment. TGFβ-mediated pathology. In alkali-injured
Mucopolysaccharidosis is a group of metabolic rodent corneas, adenoviral delivery of BMP7 into
disorders characterized by the absence of altered the cornea was shown to suppress formation of
activity of lysosomal enzyme. In this condition, myofibroblasts and infiltration of monocytes and
AV-mediated ocular delivery of human beta- macrophages. It was also shown to decrease the
glucuronidase resulted in rapid clearance of expression of collagens, TGFβ and macrophage
lysosomal storage in keratocytes. Additionally chemo-attractant protein-1 and accelerate re-
in congenital stromal corneal dystrophy, stromal epithelization. 98 Hybrid gold nanoparticle-
accumulation of mutant decorin can be treated mediated BMP7 delivery in vivo significantly
by siRNA-based gene therapy whereby mutant reduced corneal haze in an alkali and laser-
decorin formation can be prevented (Mohan et induced rabbit model. Additionally, reduction
al, unpublished data). Gene therapy could also of the inflammatory and fibrogenic responses
be used for the development of treatments for in vivo was accomplished in alkali-burn mouse
Fuch’s corneal endothelial dystrophy (FD), which corneas via adenoviral-mediated corneal delivery
is the third most common cause of blindness in of peroxisome proliferator-activated receptor-
Americans.2 FD is characterized by the formation gamma.
of bumps along the endothelium, called “guttae”,
which disrupt this corneal layer and cause corneal
Ocular Surface Disorders
swelling, corneal haze, pain, and eventually
blindness as the cornea thickens and loses its Herpes simplex virus type-1 (HSV-1) is a
transparency. 94 TGFβ signaling pathway has widespread human pathogen that can cause
been identified to play a prominent role in HSV keratitis, the leading cause of corneal
the formation of guttae94-96, and gene therapy blindness and corneal graft rejection.99, 100 Recent
approaches are currently underway in efforts to progress has been made using gene therapy
modulate this pathway to eliminate the formation to disrupt the HSV-1 genome.101-103 Following
of guttae (Mohan et al., unpublished data). One intramuscular injection of plasmids expressing
major roadblock for successful gene therapy HSV-1 glycoproteins (G, D, and gB1), marked
development for corneal dystrophies is the lack protection against keratitis pathology was
of experimental models; however, it has recently observed. Topical application of naked plasmids
been reported that a rodent disease model of encoding for interferon, tumor necrosis factor α
congenital stromal corneal dystrophy has been (TNFα), or interleukin (IL) 2, IL4, and IL10 have
identified.97 While this is an important milestone been shown to relieve HSV keratitis and prevent
for the field, much work is needed before potential scarring.
treatments can be translated to clinical application. Gene therapy has also been implicated for
the treatment of corneal ailments caused by type
Corneal Alkali Burn 1 and 2 diabetes, including corneal neuropathy
and epitheliopathy. In vitro adenovirus-mediated
Ocular alkali injuries result in corneal ulceration, transfer of cmet, a hepatocyte growth factor (HGF)
scarring, neovascularization, and opacification, receptor gene, improved HGF signaling, restored
and gene therapy approaches have been tested wild type protein expression and improved wound
for the treatment of these complications through healing.104 Research has also been conducted to
modifications of the TGFβ pathway. When Smad7 evaluate gene-based treatments for conjunctiva
gene was topically administered, Cre-adenovirus- and lacrimal gland dysfunctions (e.g. dry eye,
and Sjogren’s syndrome).105-109 Rabbit lacrimal models.116 Unfortunately, clinical translation of
glands were protected from immunopathology, these results was limited due to safety concerns,
and tear production was not increased following gene size, and cost of production of the viral
virus-mediated delivery of IL10. Additionally vectors. Nanoparticles, on the other hand, may
inhibition of TNFα resulted in reduced immune represent an alternative to viral vector gene
cell infiltration and increased tear production.105, transfer. Utilization of nanoparticles to efficiently
106
In conjunctival gene delivery investigations, reduce IOP may potentially decrease dosing
prevention of scarring has been the main focus. frequency and adverse effects and improve
Suppression of the fibrogenic response was compliance.111
reported in cultured human subconjunctival
fibroblasts and in an in vivo model of conjunctival Posterior Eye
scarring, subsequent to adenovirus-mediated
transfer of p38 mitogen-activated protein kinase, Retina
Smad7, and peroxisome proliferator-activated Mutations in some retinal pigment epithelium
receptor gamma.107-109 (RPE) genes (e.g. lecithin retinol acyltransferase
[LRAT], RPE65, and bestrophin) have been
Glaucoma associated with several blinding disorders
Glaucoma is characterized by the death of retinal including Leber’s congenital amaurosis (LCA),
ganglion cells (RGCs), which are believed to be and retinitis pigmentosa (RP).117 Other retinal
vulnerable to an increase in intraocular pressure diseases associated with RPE-related changes
(IOP). IOP is generally regulated within the include age-related macular degeneration (AMD)
anterior eye segment, and the primary cause and choroidal neovascularization.118 Secondary to
of this increase in pressure is an increase in RPE pathology, blindness typically is a result of
fluid outflow resistance through the trabecular photoreceptor degeneration and loss. There is no
meshwork. The first-line in glaucoma treatment cure for RPE-associated diseases; however, major
is the topical application of ophthalmic solution advancements have been made in the field of gene
or ointment that lowers IOP via suppression of therapy for these particular ocular conditions.
aqueous humor generation at the ciliary body, or Viral vectors (e.g. lentivirus, AV, and AAV)
enhancement of aqueous humor outflow through are capable of efficiently transferring therapeutic
the trabecular meshwork.110 However, physiologic genes to the retina and RPE.119 AAV-mediated
ocular barriers significantly limit the long-term delivery of p581PK, a 58 kD protein kinase
benefits of topical glaucoma therapeutics.111 inhibitor, was performed in a rat diabetic
Studies have identified genetic risk factors model to test this approach in the treatment of
associated with glaucoma development, and diabetic retinopathy. 120 Intravitreal injection
gene therapy approaches may achieve a more of p58IPK resulted in decreased expression
permanent solution for patients.112 Trabecular of VEGF, and TNFα, and marked decrease in
meshwork cell function has been reported to be vascularization. Additionally, based on positive
affected by mutations in myocilin.113 Research has results of extensive preclinical studies, several
also demonstrated that mutations in optineurin clinical trials are underway for the testing
increased RGC susceptibility to cellular damage of AAV-mediated therapies for LCA. 118,121-123
and death.114 While the genetic basis of glaucoma From a drug development point of view, AAV
is not entirely understood, potential target genes vectors have limitation in the treatment of
have been identified. 115 For example, AAV- retinal diseases because of their small carrying
mediated delivery of neuroprotective genes capacity. 124 For instance, AAV vectors are
successfully transduced RGCs in glaucoma unable to accommodate large genes involved in
diseases like Stargardt’s macular degeneration of the nanoparticle PK profile can enhance
(ABCA4) 125 and Usher’s syndrome type 2 tissue-specific delivery to maximize therapeutic
(USH2A),126 nor can they carry large regulatory effect while reducing non-specific delivery to
elements like LRAT. 127 Thus non-viral gene minimize adverse effects.
therapy is a major focus in the development of The physical and chemical features (e.g. size,
retinal disease therapies. charge, and surface chemistry) of nanoparticles
In RPE cell transfection, PEI-based nano determine the PK profile and consequently how
particles have mainly been studied in vitro,128-131 the particle will react within the body.136-138 Take
however, the efficacy of these vectors in RPE for example cellular internalization. Size is a key
disease models has not yet been determined. player regarding cellular uptake because it affects
Similarly, chitosan-based gene transfer has internalization mechanisms. In mammalian cells,
been shown to transfect retinal cells, 132 yet nanoparticles are internalized via phagocytosis,
therapeutic rescue of normal phenotype in macropinocytosis, or endocytosis pathways 139-141.
disease models has not been demonstrated117. Nanoparticles ~60 nm in size undergo caveolae-
PLGA nanoparticles have also been reported mediated endocytosis, those ~90 nm undergo
to safely and efficiently deliver genes to RPE clathrin-independent or caveolin-independent
cells in vitro and in vivo.133 Compacted DNA endocytosis, and those ~120 nm undergo clathrin-
nanoparticles can be targeted to many ocular mediated endocytosis. 142 This is important
tissues including the various retinal layers. 134 because the mode of entry determines the path of
In an animal model of retinitis pigmentosa (rds trafficking through subcellular compartments.137
+/-), partial rescue of photoreceptor structure and Shape and charge of nanoparticles have
function was achieved using DNA nanoparticles also been shown to affect cell internalization.
to deliver the wild-type retinal degeneration A previous study reported that non-spherical
slow gene (Rds).135 These studies support the nanoparticles were easily taken up by HeLa
potential usage of gene therapy in the treatment cells.143 Likewise, it was also reported that rod-
of retinal disease. like mesoporous silica nanoparticles 144 and iron
oxide nanoworms 145 displayed enhanced cellular
uptake compared to spherical counterparts.
NANOPARTICLE However, other studies have demonstrated that
PHARMACOKINETICS: spherical gold146 and polymeric nanoparticles147
CONSIDERATIONS FOR GENE were internalized more efficiently than non-
THERAPY DEVELOPMENT AND spherical counterparts. Additionally in contrast to
CLINICAL USE anionic particles, cationic nanoparticles typically
have increased cellular uptake.148-150 Polarity of a
As described above, there are several different particle (hydrophobic vs. hydrophilic) also plays
types of nanoparticles. Consequently, each type a role in the cellular uptake, as well as the mean
has a unique pharmacokinetic (PK) profile. residence time and clearance.136
To better understand and predict efficacy As with most novel technologies, there are
and toxicity before clinical utilization of any rising concerns about the potential side effects
given nanoparticle system, it is necessary to associated with the use of nanoparticles to deliver
understand the PK and biodistribution. This therapeutic molecules. Therefore, to better grasp
involves longitudinal monitoring of particle the risks associated with nanoparticle exposure,
concentration in critical tissues until the routes of entry and cytotoxicity, extensive studies
elimination phase, and includes parameters should be conducted. Unfortunately the same
like: half-life, mean resident time, maximum features that make nanoparticles attractive for
concentration, and clearance. 136 Optimization nanodelivery, could also lead to cytotoxicity. The
small magnitude of nanoparticles, for example, 2. Frick KD, Gower EW, Kempen JH, Wolff JL.
could make them very reactive within the cell.151 Economic impact of visual impairment and
Small size may also allow nanoparticles to blindness in the United States. Arch Ophthalmol.
enter and deposit in major organs (i.e. the skin, 2007;125(4):544-50.
3. Mohan RR, Rodier JT, Sharma A. Corneal
intestines, blood and lungs), which could result
gene therapy: basic science and translational
in severe adverse reactions.152-154 Consequently, perspective. Ocul Surf. 2013;11(3):150-64.
nanoparticle toxicity is also dependent on the 4. Bainbridge JW, Smith AJ, Barker SS, Robbie S,
body’s ability to properly clear deposited particles Henderson R, Balaggan K, et al. Effect of gene
from different organs. It is therefore necessary to therapy on visual function in Leber’s congenital
take into consideration the risks/benefits ratio in amaurosis. N Engl J Med. 2008;358(21):2231-9.
nanomedicine applications. 5. Hauswirth WW, Aleman TS, Kaushal S,
Cideciyan AV, Schwartz SB, Wang L, et al.
Treatment of leber congenital amaurosis due to
CONCLUSIONS RPE65 mutations by ocular subretinal injection
of adeno-associated virus gene vector: short-
Nano-ophthalmology is a translational field and term results of a phase I trial. Hum Gene Ther.
its earliest impact will likely include areas like 2008;19(10):979-90.
biopharmaceuticals (e.g. therapeutic molecule 6. Maguire AM, High KA, Auricchio A, Wright JF,
Pierce EA, Testa F, et al. Age-dependent effects
discovery and delivery).155 Consequently, gene
of RPE65 gene therapy for Leber’s congenital
therapy is a very promising innovative tool that amaurosis: a phase 1 dose-escalation trial.
could aid in the development of preventative Lancet. 2009;374(9701):1597-605.
care/treatments for currently incurable ocular 7. Maguire AM, Simonelli F, Pierce EA, Pugh EN,
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resolve these incurable problems, steps should amaurosis. N Engl J Med. 2008;358(21):2240-8.
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ChapteR 21
Ocular Adverse Effects of Systemically
Administered Drugs
OVERVIEW interpreted, effects of drug interactions at the

blood-ocular site still need to be determined and
A number of common eye diseases ranging from this could possibly throw light on the failure
simple corneal infections to retinoblastoma are or unusual responses to various therapeutic
currently being targeted by medications delivered regimens. This chapter summarises available
either systemically or through topical ophthalmic literature on the ocular side effects of some
preparations. The adverse effects associated with commonly prescribed medications for the
the drugs used for diagnostic and therapeutic treatment of systemic diseases with an attempt
purposes in ophthalmology have already been to understand the pharmacology behind their
discussed in preceding chapters. unusual effects.
Ironically, drugs prescribed for several
systemic diseases are known to precipitate
ocular toxicity upon chronic use.1 Some of these OCULAR ADVERSE EFFECTS OF
adverse effects include acuity changes, dry DRUGS ACTING ON AUTONOMIC
eye complication, disturbances in color vision, NERVOUS SYSTEM
alteration of lens proteins, changes in aqueous
humor dynamics and damage to nervous tissue, Drugs acting on autonomic nervous system are
viz. retina.2 This means that these molecules used to treat a myriad of symptoms ranging from
not only cross the transport barriers, but also appetite disorders, urinary incontinence, motion
have the propensity to interfere with the normal sickness and glaucoma. Amphetamine used in
physiological functions in the eye such as retinal the treatment of Attention Deficit Hyperactivity
neurotransmitters, which reflects in the alteration Disorder is known to precipitate angle-closure
of vision perception.3 However, these adverse glaucoma due to its propensity to cause pupillary
effects could also be due to some unknown dilation.4 Benztropine is widely used as a second-
action on the cerebral cortex, which needs to be line treatment of Parkinsonism. Though there
ascertained. Clearly, these drugs are capable of is no widely available information about the
crossing the blood-brain/ blood-ocular barriers prevalence of this disease in developing countries,
through their unknown effects on the transporters. certain populations show high prevalence.
Interaction between co-administered drugs This drug has also been used to reverse symptoms
further complicates the scenario. Drugs could of oculogyric crisis (ocular pain and sustained
interact at the site of their absorption or at the upward gaze) caused by the combination
binding site. While the drug interactions at therapy of imipramine, methylphenidate and
the systemic level are widely recognized and valproic acid in the treatment of depression and
Ocular Adverse Effects of Systemically Administered Drugs 305
epilepsy.5 Benztropine when given in combination OCULAR ADVERSE EFFECTS OF
with phenothazine or a butyrophenone results DRUGS ACTING ON CENTRAL
in difficulty in near vision and reduced
NERVOUS SYSTEM
accommodation, the extent of impairment
ranges from 40–100%.5-6 Mydriasis, decreased The drugs acting on the CNS cross the blood-brain
vision, loss or paralysis of accommodation, barrier and are associated with neural adverse
diplopia, angle-closure glaucoma, decreased effects. Retina, the neurosensory part of the eye,
tolerance to contact lenses, subconjunctival/retinal originates as a direct projection of the optic stalk
hemorrhages secondary to drug induced anemia during early development. It is protected from the
have also been reported with the use of this drug.7 adverse effects of most of the drugs as they are
Benzhexol, an antimuscarinic drug, also used prevented from entering the ocular compartment
in the treatment of Parkinsonism, is known to due to the presence of transporter molecules both
cause rise in intraocular pressure.5 Beta-blockers at the posterior and anterior sides. However,
are one of the firstline treatment approaches many psychotropic medications are reported to
overcome the transporter barriers and produce
for hypertension. Patients on treatment with
numerous diverse and unwanted ocular adverse
metoprolol and pindolol develop eye discomfort
effects.
resulting in poor patient compliance.8
Phenothiazines are one of the widely
Anticholinergic or adrenergic agents most prescribed centrally active drugs. They are
commonly induce “pupillary block” angle-closure used as preanesthetic medication, to alleviate
glaucoma.9 Nebulized ipratropium bromide and anxiety and to provide additional sedation by
salbutamol routinely prescribed for chronic synergistic action with co-administered sedatives
obstructive airways disease are also known to or analgesics. Eyelid and kerato-conjunctival
precipitate angle-closure glaucoma.10 disorders are widely reported as adverse effects.24
Antimuscarinic agents are used in the treatment Chlorpromazine, one of the phenothiazines,
of overactive bladder.11,12 Oxybutynin is one of is known to cause abnormal pigmentation of
the commonly prescribed drugs for overactive eyelids, cornea and conjunctiva. It also results
bladder in elderly. This drug is reported to reduce in corneal edema leading to visual impairment.
accommodation amplitude and precipitate acute Chronic use of high doses of chlorpromazine
angle-closure glaucoma. In children, this drug is and thioridazine is reported to cause lenticular
frequently (56%) prescribed for the treatment of opacification and retinopathy.24,25 Carbamazepine
enuresis.13 Esotropia has been reported in a 5 year has been associated with deficiency in color vision
and reduced contrast sensitivity.26-28 Nystagmus,
old girl (with no previous history) while being
diplopia, and extraocular muscle palsies have
treated for enuresis. Oxybutynin also produces
also been reported when this drug was used in
dose-dependent effect on near vision. 1,13-21
the treatment of epilepsy.1 In-utero exposure
Solifenacin is another routinely prescribed drug to this drug has resulted in congenital ocular
for overactive bladder, which is reported to cause malformations in the fetus.1
dry eye and blurred vision.22,23 Depression is one of the most common
To summarize, most of the drugs acting on the disorders of the central nervous system which
autonomic nervous system seem to precipitate affects approximately 1 in 18 (5%) of the world
adverse effects on the anterior segment of the population in general. It is estimated that an
eye, particularly the ciliary body, iris and lens. individual suffers depression at least once in
The most common adverse effect associated with a lifetime and there is a lifetime risk of 7% of
these medications is angle-closure glaucoma and depressive episode in men and about 20% in
decrease in accommodation (Table 21.1). women. On an average, at least 10% of the
Table 21.1 Ocular adverse effects of drugs acting on autonomic nervous system
Drug/class Therapeutic uses Ocular adverse effects

Amphetamine, Appetite suppression Pupillary-block glaucoma
Hydroxy amphetamine
Benzatropine Muscular cramps Mydriasis, decreased vision, loss or paralysis
Parkinson disease of accommodation, diplopia, pupillary-block
glaucoma, decreased tolerance to contact lenses,
subconjunctival/retinal hemorrhages secondary to
drug-induced anemia
Beta-blockers Hypertension, angina, Dry eye, diplopia, decreased intraocular pressure,
arrhythmia, myocardial visual hallucination, reduced perfusion of the optic
infarction nerve head resulting in glaucoma progression
Demecarium Glaucoma Anterior subcapsular granular cataract
Echothiophate
Oxybutynin chloride Urinary incontinence Dry eye, blurred vision, increased risk of angle-
closure glaucoma
Pralidoxime Organophosphate poisoning Iritis
Prazosin Hypertension Blurred vision, reddened sclera
Salbutamol Asthma Mydriasis, decreased vision, conjunctival
hyperemia and chemosis due to blood vessel
dilation, petechial conjunctival hemorrhages
Scopolamine Motion sickness Relative pupillary-block glaucoma
Solifenacin succinate Urinary incontinence Dry eye, blurred vision
Tamsulosin Benign hypertrophy of Intraoperative floppy iris syndrome during cataract
prostate surgery
Tolterodine tartrate Urinary incontinence Blurred vision, xerophthalmia
affected population of depressed individuals is with narrow irido-corneal angles may get an acute
prescribed medications. Lithium is one of the attack of glaucoma with TCA treatment.26
principle drugs used as a mood stabilizer.29 This Epilepsy is another major class of disorder
drug is associated with keratin deposits in the treated with centrally-acting medications. Drugs
cornea.24,30 It affects sodium transport and causes frequently prescribed under this category include
eye irritation.24 Some cases of exophthalmos and phenytoin, vigabatrin and valproic acid. Diplopia,
papilledema have also been reported.25 Corneal blurred vision, nystagmus, extraocular muscle
deposits and keratitis has been observed with palsies, disturbances in eye movement and
amantadine and amiodarone.31 Diffuse and fine color disturbances are frequently reported side-
keratin deposits were observed in the central effects with antiepileptic drugs. Vigabatrin is
part of corneal endothelium. Monocyclic amines a well-known drug extensively employed for
were shown to accumulate in the eyes of animals the treatment of childhood epilepsy and partial
even after acute administration. 32 Tricyclic seizures.26 However, this drug is known to cause
antidepressants (TCAs) may affect the uveal tract visual field defect in approximately one-third of
and in some cases transient mydriasis has been the patients as a result of retinal toxicity. ERG
reported with the use of these drugs.25 TCAs also changes with vigabatrin have been observed in
interfere with accommodation and cause blurred humans reflecting bilateral concentric visual field
vision in up to one-third of the patients. Patients loss, including contrast sensitivity and abnormal
color perception.33 Peripheral defects are more precede its classical anticonvulsant action. This
prominent than central.3,26 Visual field defects drug may have GABAergic effect on the visual
have also been reported with other antiepileptic field. Mydriasis induced angle-closure glaucoma
drugs such as phenytoin and carbamazepine.1, is a serious dose-dependent adverse effect also
27,28
Bilateral concentric visual field loss and noted with this drug. Unusually, glaucoma
color vision defects have also been reported with occurs due to an allergic-type of reaction wherein
valproic acid.34 Sodium valproate, phenytoin and the structures of the lens and ciliary body are
carbamazepine possess the propensity to cause displaced. Additional adverse effects include
congenital ocular malformations in fetus and thus ocular dystonia, uveal tract disorders, myopia,
should be avoided during pregnancy.1 Lorazepam, eye movement disorders, color abnormalities and
a classical benzodiazepine co-prescribed as an reduced contrast discrimination.1
anti-anxiety treatment to epileptic patients, is Angle-closure glaucoma and uveal tract
also reported to influence visual perception. disorders are one of the most frequent adverse
An analog molecule, alprazolam, may cause effects seen with many typical anti-psychotics and
glaucoma. Benzodiazepines are also known to selective serotonin reuptake inhibitors (SSRIs).24
cause disturbance in eye movements.24, 35,36 Almost all the drugs belonging to this class are
Antipsychotics are known to produce several known to cause transient mydriasis leading to
ocular adverse effects such as mydriasis, ocular glaucoma in predisposed patients. While low-
dystonia, angle-closure glaucoma, uveal tract potency antipsychotics could lead to problems
disorders, hypersensitivity of unknown origin, with accommodation, ocular dystonias have been
eye movement disorders and abnormality in color observed with high-potency drugs.
perception.24 In this regards, particular mention This reaffirms that these drugs have potential
needs to be given to a low-potency antipsychotic, to cross the blood-ocular barrier and interfere with
topiramate. Topiramate originally used to treat the physiological activities of the ocular tissue.
epilepsy in children was later known to enhance Several of the adverse effects such as glaucoma
GABAergic transmission and cure cases of are vision-threatening but often patients fail to
bipolar disorder.26 Though the exact mechanism of recognize or describe the symptoms appropriately.
action of this drug remains unknown, psychiatrists Therefore, neurologists must make adequate
and neurologists believe that the drug has observations while prescribing these drugs (Table
additional mood stabilizing properties which 21.2).
Table 21.2 Ocular adverse effects of drugs acting on central nervous system
Alprazolam, clonazepam, Epilepsy, anxiety and Blurred vision, diplopia, burning, tearing, allergic
midazolam panic conjunctivitis, angle-closure glaucoma, decreased
corneal reflex and accommodation
Amitriptyline Depression Cycloplegia, dry eye, diplopia, increased intraocular

pressure, toxic amblyopia, pupillary-block glaucoma
Codeine Cough Miosis, decreased vision, myopia, lid dermatitis, iritis
Dexmethylphenidate Attention deficit Blurred vision, visual changes

hyperactivity disorder
Count...
Count...
Diazepam Anxiety Allergic conjunctivitis, blurred vision, dry eye, diplopia,
decreased accommodation, mydriasis, retinal
hemorrhages, pupillary-block glaucoma
Ethanol Methanol poisoning Toxic neuropathy, diplopia
Ethosuximide Epilepsy Dyskinesia, photophobia, myopia
Felbamate Epilepsy Diplopia, nystagmus

Gabapentin, Epilepsy, migraine, Allergic conjunctivitis, mydriasis, visual disturbances,
lamotrigine, bipolar affective disorder secondary angle-closure glaucoma, nystagmus,
topiramate ocular hyperemia, macular edema, uveitis
Isocarboxazid Depression Photophobia
Levetiracetam Epilepsy Diplopia
Lithium Acute mania Contact lens intolerance, downbeat jerk nystagmus,
diplopia, decreased accommodation, cycloplegia,
blurred vision, papilledema
LSD, mescaline, To alter mood and Diplopia, cycloplegia, miosis
marijuana, hashish, behavior (hallucinogen)
psilocybin
Morphine, opium, heroin Cancer pain Miosis, iritis
Methadone Cough Decreased vision, pupillary changes, talc retinopathy
Methylphenidate Concentration and Mydriasis, decreased accommodation, blurred vision,
attention deficits visual hallucination
Oxcarbazepine Epilepsy Diplopia, blurred vision
Phenobarbitone Insomnia Ptosis, nystagmus, mydriasis, cycloplegia,
Anxiety disturbances of color vision, glare, extraocular palsies
Phenothiazines Schizophrenia Dry eye, blue conjunctiva, diplopia, endothelial
pigmentation, mydriasis, cycloplegia, anterior
subcapsular cataract, exacerbation of open-angle
glaucoma, blurred vision, blue-yellow color vision
Phenytoin Epilepsy Allergic conjunctivitis, cataract, color vision
Carbamazepine disturbances, blurred vision, secondary angle-closure
glaucoma, downbeat nystagmus, ocular hyperemia,
macular edema
Primidone Epilepsy Diplopia, nystagmus
Selective serotonin Obsessive compulsive Keratitis sicca, conjunctivitis, diplopia, blurred
reuptake inhibitors disorder, vision, photophobia, angle-closure glaucoma, eyelid
(SSRIs) panic disorder, changes, increased extraocular movements during
premenstrual syndrome sleep
Tiagabine Epilepsy Abnormal color perception, blurred vision, nystagmus,
diplopia
Topiramate Epilepsy Diplopia, acute myopia and angle-closure glaucoma
Valproic acid Epilepsy Oculomotor disturbances

Venlafaxine Depression Blurred vision
Vigabatrin Epilepsy Diplopia, nystagmus, peripheral visual field loss, color
perception abnormalities, retinal abnormalities, optic
nerve pallor, visual electrophysiological changes,
reduced contrast sensitivity, reduced ocular blood flow
OCULAR ADVERSE EFFECTS the outflow facility in experimental rabbits.39

OF DRUGS ACTING ON Amlodipine is known to cause conjunctival
chemosis while chronic use of nifedipine for
CARDIOVASCULAR SYSTEM the treatment of hypertension is associated with
Cardiovascular diseases are considered world’s substantial reduction in visual function. 40,42
largest killers. Over 80% of deaths related Both nifedipine and captopril are believed to
to these diseases are known to occur in the cause ocular vasodilatation, which could lead
developing nations. According to disease estimate to glaucoma although sufficient clinical reports
taken in year 2000, approximately 29 million are lacking.43 Another category of drugs widely
people were suffering from CVS diseases in used in the treatment of hypertension are beta-
India.37 Angiotensin Converting Enzyme (ACE) blockers. They tend to reduce tear lysozyme
inhibitors, calcium channel blockers, diuretics, levels along with total amount of tear secretion.
cardiotonics, nitrates and quinidine are the most Patients generally complain of ocular irritation
frequently prescribed drugs for the treatment of and exhibit dry eye symptoms. Contact lens
hypertension, ischemic heart disease, arrhythmia intolerance may also develop.
and cardiac failure. Amiodarone is one of the frequently
Of the various classes, ACE inhibitors are prescribed drugs for the treatment of arrhythmia.
considered by far the safest category of drugs Since the drug seems to have a dual action
for the treatment of hypertension and maintain (beta-blocker and calcium channel blocker),
a high popularity among physicians. The only it is generally the drug of choice when all
ACE inhibitor with reported ocular side effect other treatment modalities fail. However,
is fosinopril. Hydrochlorothiazide, a diuretic this drug is known to be a photosensitizer.
also used in the treatment of hypertension, is Keratopathy of the entire cornea, including the
associated with visual changes and yellowing endothelium and lens, is observed in patients
of the eyes. However, it needs to be ascertained because of its tendency to increase lipid
whether the side effect is due to the drug or its storage. Corneal deposits are seen in most of
salt form. the patients who receive amiodarone treatment
Digitalis, a cardiotonic, used for the treatment for more than 6 months. Some of the other
for congestive heart failure is now the last resort abnormalities reported are maculopathy, optic
for treatment. It has a tendency to cause photopsia neuropathy (high incidence of 1.3% to 1.8%),
and color vision abnormalities. Approximately, and optic neuritis. Optic neuropathy is, however,
11–25% of the patients treated with this drug have reversible with the discontinuation of drug.31,44,45
expressed ocular symptoms such as abnormal Diuretics are another drug class used for the
visual sensations or flickering vision in addition treatment of hypertension as well as congestive
to abnormal color vision. High concentrations heart failure. Most of the drugs are generally
of the drug accumulate in the retina and choroid considered safe. However, few rare reports on
indicating its easy entry through the retinal the side-effects are noted. One of the rare reports
transport processes. Digitalis also inhibits the is association of furosemide with blurred vision
sodium potassium (Na+, K+) transporter in the and xanthopsia.
ciliary epithelium resulting in alteration in Angle-closure glaucoma in predisposed
aqueous humor dynamics.38 patients generally develops upon treatment
Increase in intraocular pressure is also with nitrates due to their vasodilating action.
observed with the use of calcium channel Nitroglycerines are known to cause color vision
blockers and most notably with ditliazem. 39 disturbances, changes in intraocular pressure
Topical instillation of verapamil, diltiazem and and eyelid dandruff. Some of the other adverse
nifedipine has also been demonstrated to reduce effects, which require mention are blurred vision,
eyelid swelling, cataract with losartan; allergy of OCULAR ADVERSE EFFECTS OF LIPID
lids and conjunctiva, decreased vision, decreased LOWERING AGENTS
IOP, subconjunctival/ retinal hemorrhages
with methyldopa; optic neuritis, visual field HMG-CoA reductase inhibitors, also referred to
loss, abnormal retinal pigmentation and vision as “statins”, act by blocking the rate-limiting step
disturbances with quinidine (Table 21.3). in cholesterol biosynthesis and are, therefore,
Table 21.3 Ocular adverse effects of drugs acting on cardiovascular system

ACE inhibitors Hypertension, congestive heart Conjunctivitis, photosensitivity, loss of vision, decrease in
failure, diabetic nephropathy intraocular pressure, amblyopia, diplopia, myopia
Amiodarone Arrhythmias Anterior subcapsular cataract, yellow or brown deposits
in conjunctiva, blurred vision, colored halos, dry eye,
nystagmus, whorl-like corneal deposits, optic neuropathy,
photophobia
Amlodipine Hypertension Abnormal vision, conjunctivitis
Diltiazem Systemic hypertension, angina Amblyopia, photosensitivity, hallucinations, irritation
pectoris periorbital edema, lacrimation, subconjunctival and
retinal hemorrhage
Digoxin Congestive heart failure Corneal edema, diplopia, mydriasis, decreased
intraocular pressure, yellow vision, flickering vision
Diuretics Congestive heart failure, Dry eye, myopia, color vision disturbances, allergy of
hypertension lids and conjunctiva, decreased intraocular pressure,
subconjunctival or retinal hemorrhages
Doxazosin, Hypertension Abnormal vision, photophobia, conjunctivitis
Terazosin
Hydralazine Hypertension Rarely cause appearance of inflammatory cells in the
vitreous and macular edema
Nitrates Angina pectoris Transient blurred vision
Isosorbide
Losartan Hypertension Blurred vision, eyelid swelling, cataract
Methyl dopa Acute or severe hypertension Allergy of lids and conjunctiva, decreased vision,
decreased intraocular pressure, subconjunctival or retinal
hemorrhages
Nifedipine, Hypertension, angina, Vision changes, ocular irritation, periorbital and
verapamil heart failure angioneurotic edema, lacrimation, pain, lid edema,
conjunctival chemosis, erythema, conjunctivitis, rotary
nystagmus, photosensitivity
Nitroglycerine Angina pectoris Yellow/ blue halos, alteration of intraocular pressure,
eyelid dandruff
Quinidine Arrhythmias Color vision distortions, scotoma, optic neuritis, visual
field loss, abnormal retinal pigmentation
effective in lowering the plasma cholesterol optic neuritis, decreased vision, toxic amblyopia,
levels.46 The Physicians Desk Reference in the photophobia, extraocular muscle paresis and
USA mentions ocular hemorrhages as a possible myopia.54, 55
side effect for some of the statins.47 Lovastatin,
a cholesterol lowering agent isolated from a
strain of Aspergillus terreus, is associated with
OCULAR ADVERSE EFFECTS OF
a high rate of lens opacities.48 Evidences suggest THERAPEUTIC HORMONES
that statins reduce platelet aggregation and
Bisphosphonates are mainly used in treatment of
decrease thrombin formation and, therefore, could
osteoporosis and inhibition of bone resorption in
contribute to ocular hemorrhages.49 Atorvastatin
postmenopausal woman as well as management
is found to be associated with several ocular
of hypocalcaemia of malignancy. Alendronate
adverse effects such as blurred vision, dry eye,
was shown to cause inferonasal nodular scleritis
increase in intraocular pressure and development
after five weeks of treatment.56 After intravenous
of intraocular hemorrhage.50 Studies have reported
administration of pamidronate disodium, cases
reversal of ptosis in patients upon discontinuation
of unilateral and bilateral scleritis have been
of drug. Incidences of diplopia, ptosis and
reported. Repeated drug exposure may lead
ophthalmoplegia have also been reported
to blurred vision, non-specific conjunctivitis,
with fluvastatin, rosuvastatin, pravastatin, and
ocular pain, episcleritis and bilateral anterior
simvastatin.51 Niacin is another antihyperlipidemic
uveitis.57,58 Combination of esterified estrogen
drug associated with ocular adversities such as
and methyl testosterone produces significant
dry eye and cystoid macular edema in addition to
increase in intraocular pressure in postmenopausal
the symptoms of lid edema and blurred vision.52
women.59 Tamoxifen treatment is reported to lead
to perifoveal white refractile deposits associated
OCULAR ADVERSE EFFECTS OF with pigmentary changes, cystoid macular edema
ANTI-HYPERGLYCEMIC AGENTS and changes in cornea. Patients receiving high
dose of tamoxifen develop extensive retinal
Diabetic macular edema is associated with lesions and macular edema with visual impairment
glitazones.53 Insulin and sulfonylureas may give whereas low doses of drug for prolonged periods
rise to crystalline lens changes and refractive error may lead to extensive retinal changes. Authors
shifts in the absence of blood glucose variation. have observed isolated retinal crystals in patients
Other adverse effects may include diplopia, treated with this drug. (Table 21.4)60,62
Table 21.4 Ocular adverse effects of therapeutic hormones

Alendronate Osteoporosis, Anterior uveitis, retinitis, vision changes, lacrimation, photo-
metastatic bone pain phobia, episcleritis, scleritis, non-specific conjunctivitis
Dextrothyroxine Hypothyroidism Conjunctival hyperemia, pseudotumor cerebri, visual
Levothyroxine hallucination
Estradiol Estrogen replacement Contact lens intolerance
Estrogen, Premenstrual tension, Dry eye, loss of vision, retinal vascular disorders,
progestogens, postmenopausal pseudotumor cerebri, decreased tolerance to contact lenses,
medroxyprogesterone hormone replacement papilledema
Levonorgestrel Conception Diplopia, dry eye, mydriasis, macular edema, vascular
Ethinyl estradiol (oral contraceptive) occlusion, pseudotumor cerebri, papilledema, myopia
Tamoxifen Breast cancer Posterior subcapsular cataract, deposits in cornea, crystalline
dot like yellowish deposits in surrounding area of macula
OCULAR ADVERSE EFFECTS Indomethacin prescribed for rheumatoid arthritis

OF ANALGESIC AND ANTI- is also found to cause severe ocular toxicity
leading to decreased vision, diplopia, blue-yellow
INFLAMMATORY AGENTS color vision, lid or conjunctival erythema, toxic
Ocular toxicity is associated with widely used amblyopia, corneal toxicity and optic neuritis.70
non-steroidal anti-inflammatory drugs (NSAIDs). Dexamethasone used for rheumatoid arthritis,
Aspirin therapy is known to cause dry eye, blurred may cause blue conjunctivitis, diplopia, stromal
vision and subconjunctival hemorrhages. Aspirin, opacities, mydriasis, posterior subcapsular
in combination with warfarin therapy may lead cataract, increased intraocular pressure, myopia,
to hyphema and retinal detachment.63 Ibuprofen, retinopathy, impaired colour vision, reduced
another routine over the counter medicine, visual acuity, visual field loss and blurred
is known to cause centrocecal field defects, vision. 71 Beclomethasone, hydrocortisone,
reduced visual acuity, and in some cases optic methylprednisolone and prednisone are widely
neuritis with defects in visual field.64,65 COX-2 used glucocorticoids, which cause mydriasis,
inhibitors such as celecoxib and rofecoxib may posterior subcapsular cataract, increased
lead to temporary blindness, visual field defects, intraocular pressure, delayed corneal wound
scotoma, teichopsia, blurred vision, decreased healing, central serous chorioretinopathy and
vision and abnormal vision.66 Allopurinol, an ocular hypertension.72-74 Along with these optic
anti-hyperuricemic drug used in treatment of nerve related disorders, retrobulbar neuritis or
gouty arthritis, is associated with cataract.67 Gold papilledema secondary to pseudotumor cerebri
administered for the treatment of rheumatoid are found to be associated with different NSAIDs
arthritis causes ocular and corneal chrysiasis such as ibuprofen, indomethacin, diflunisal (Table
(deposition of gold particles in ocular tissue).68,69 21.5).75
Table 21.5 Ocular adverse effects of analgesic and anti-inflammatory agents

Allopurinol Gout Cataracts, macular changes
Aspirin Post-myocardial Dry eye, transient blurred vision, subconjunctival hemorrhages,
infarction, rheumatoid post-surgical retinal bleeds
arthritis
Beclomethasone, Inflammation Mydriasis, posterior subcapsular cataract, increased intraocular
hydrocortisone, allergic disorders pressure, delayed corneal wound healing, papilledema secondary
methyl predinosolone, to pseudotumor cerebri
prednisone
Dexamethasone Rheumatoid arthritis Blue conjunctivitis, diplopia, stromal opacities, mydriasis, posterior
subcapsular cataract, increase in intraocular pressure (secondary
open-angle glaucoma), myopia, retinopathy, impaired color vision,
pseudotumor cerebri, visual acuity/ visual field loss, blurred vision
Gold Rheumatoid arthritis Ocular chrysiasis, nystagmus, gold deposits in conjunctiva, anterior
subcapsular cataract, retinal hemolysis, blurred vision
Ibuprofen Rheumatoid arthritis, Decreased vision, scotomata, lid or conjunctival erythema,
osteoarthritis photophobia
Indomethacin Rheumatoid arthritis Decreased vision, diplopia, blue-yellow color vision, lid or conjunctival
erythema, toxic amblyopia, corneal toxicity, optic neuritis
Mometasone Bronchial asthma Increased intraocular pressure, progressing glaucoma, tearing
Valdecoxib, Rofecoxib Arthritis Vision changes, conjunctivitis, yellowish eyes, temporary blindness
OCULAR ADVERSE EFFECTS OF Cephaloridine therapy has been associated with

ANTIHISTAMINES unilateral retinal pigmentosa leading to extinction
of ERG and total irreversible blindness after
Systemic loratidine and cetrizine have been subconjunctival and intracameral injection in few
associated with ocular dryness, decreased tear film cases.83 Intravitreal injection of cefotetan resulted
breakup time and conjunctival staining.76 Dry eye, in mild degeneration of photoreceptor outer
decreased accommodation, increase in intraocular segments and sporadically in cataract formation.84
pressure and even the pupillary-block glaucoma There are some evidences of retrobulbar neuritis
have been reported with diphenhydramine and with chloramphenicol therapy.85 In experimental
chlorpheniramine (Table 21.6).77 models, antifungal agent amphotericin-B causes
inflammatory changes in the anterior chamber and
corneal epithelial defects when given intravitreally
OCULAR ADVERSE EFFECT OF or topically.86 Oral voriconazole, an antifungal
ANTIULCER DRUGS agent, leads to photopsia and color changes in
some patients.87 Quinine is known to produce
Omeprazole, a proton pump inhibitor, is a acute visual loss.88 Antimalarial drugs like systemic
commonly used drug for the treatment of peptic hydroxychloroquine and chloroquine related retinal
ulcer. Intravenous use of omeprazole can cause toxicity is well documented. Hydroxychloroquine
loss of vision.78 Pirenzepine is an anticholinergic causes irreversible retinopathy. 89-92 Optic
agent with selective M1 receptor antagonist action. neuropathy has been reported with isoniazid and
The clinically effective doses of this drug can ethambutol.93 Ethambutol may produce optic
cause dry mouth and blurred vision.79 Ranitidine neuropathy if the daily dosage exceeds 15 mg/kg.94
may cause impaired color vision, angioneurotic Rifampin is associated with blepharoconjunctivitis
edema, hyperemia and urticaria of lids and and optic neuritis.95 Cystoid macular edema is seen
conjunctivitis. in HIV patients who are receiving highly active
antiretroviral therapy (HAART). Intravenous
cidofovir precipitates anterior uveitis (Table
OCULAR ADVERSE EFFECTS OF 21.7).96,97
ANTIMICROBIAL AGENTS
Aminoglycosides, especially gentamicin, has OCULAR ADVERSE EFFECTS OF
been associated with cases of retinal toxicity ANTICANCER AGENTS
and initial loss of function.80 There are reported
cases of diplopia with fluoroquinolone therapy.81 Treatment with anticancer drugs is also
Phototoxicity and neurotoxicity have been associated with several ocular adverse effects.
reported with the use of ciprofloxacin, ofloxacin, Methotrexate causes ocular irritation and
trovafloxacin, moxifloxacin and pefloxacin.82 cataracts. 98 Tamoxifen and interferons cause
Table 21.6 Ocular adverse effects of antihistaminics

Diphenhydramine Seasonal allergies Dry eye, anisocoria, decreased accommodation, increased
Chlorpheniramine intraocular pressure, pupillary-block glaucoma, retinal
hemorrhages, blurred vision, mydriasis, diplopia
Orphenadrine Parkinsonism Decreased vision, diplopia, decreased accommodation,
mydriasis, subconjunctival/retinal hemorrhages secondary to
drug-induced anemia
Table 21.7 Ocular adverse effects of antimicrobial agents
Acyclovir Genital herpes simplex, chicken pox Visual hallucinations, periocular edema
Amphotericin-B Oral and cutaneous candidiasis Greenish discoloration of cornea, retinal

necrosis
Ampicillin UTI, gonorrhea, meningitis Eyelid erythema multiforme, conjunctivitis
Cephalosporins Respiratory, urinary and soft tissue Nystagmus, decreased vision, allergy of
infection lids and conjunctivitis
Chloramphenicol Typhoid fever, influenza Toxic amblyopia, retrobulbar neuritis
Chloroquine, Malaria, rheumatoid arthritis Bull’s eye maculopathy, blue-yellow color
hydroxy chloroquine vision, optic atrophy, ptosis, nystagmus,
whorl-like epithelial deposits in cornea,
cycloplegia, whitening of lashes
Didanosine HIV Retinal changes, night blindness, optic
neuritis
Enfuvirtide HIV Conjunctivitis
Erythromycin Respiratory infection Colour vision, allergy of lids and
conjunctivitis
Ethambutol Tuberculosis Retrobulbar optic neuritis, green-red color
vision, diplopia, mydriasis
Fluoroquinolones Urinary tract infections (UTI), Photosensitivity
gonorrhea, typhoid, respiratory
infections, soft tissue and bone
infections
Gentamicin UTI, pneumonia Intraretinal hemorrhage, cotton wool spots,
opaque retina, superficially edematous
retina
Isoniazid Tuberculosis Optic neuritis, green-red color vision,
accommodation impairment
Linezolid Hospital acquired pneumonia, febrile Dyschromatopsia, ecocentral scotomas,
neutropenia decreased visual acuity
Quinine Malaria, nocturnal leg cramps Decreased vision, optic nerve damage,
venous congestion, retinal changes and
arteriolar constriction
Rifampin Tuberculosis Blepharoconjunctivitis, optic neuritis
Sulfonamides Bacterial infection Eye lid edema, conjunctivitis, myopia,

retinal hemorrhages, optic neuritis
Tetracyclines Venereal disease, plague Retinal hemorrhages, pseudotumor
cerebri, dark deposits, paresis, diplopia
Zidovudine, lamivudin, HIV Colour vision, diplopia, nystagmus, cystoid
abacavir macular edema, hypertrichosis, urticaria,
eyelid rashes, eyelid and conjunctival
hyperpigmentation
considerable ocular morbidity, visual losses persistent dry eye syndrome have also reported
even in therapeutic doses. 99 Taxanes cause (Table 21.9).103,104
capillary leak syndrome and hydroxyurea
causes ulceration and pseudodermatomyositis.100
High doses of systemic chemotherapy such as OCULAR ADVERSE EFFECTS OF
carmustine and mitomycin can cause qualitative ANTICOAGULANTS
changes in the tear film indicating damage to
Warfarin is the most commonly used oral
the corneal and conjunctival epithelium (Table
anticoagulant. Its ocular side effects include
21.8).101
ocular bleeding like hyphema, hemorrhagic tears,
subconjunctival, vitreal, retinal or choroidal
OCULAR ADVERSE EFFECTS OF hemorrhages. 105,106 Angle closure glaucoma
DRUGS USED IN DERMATOLOGICAL has also been reported as a complication of
warfarin treatment. 107 Spontaneous anterior
DISORDERS chamber hyphema can occur in any patient on
Acitretin is an active metabolite of etretinate anticoagulant treatment. Cases have been reported
used for systemic treatment of psoriasis. It for nontraumatic108retrobulbar hematoma due to
has largely replaced etretinate because of its warfarin toxicity.
acceptable pharmacokinetics. However, it
causes blepharoconjunctivitis with lymphocyte OCULAR ADVERSE EFFECTS OF
infiltration and involves keratinized epithelial
VITAMINS
cells.102 Isotretinoin is an isomer of tretinoin (all
Trans vitamin-A acid). Several ocular adverse Isotretinoin (13-cis-retinoic acid) is associated
effects have been reported with the use of with ocular complications like dryness of
isotretinoin and include abnormal meibomian eye, blepharitis, conjunctivitis, decreased tear
gland secretion, blepharoconjunctivitis, corneal break-up time (BUT) and alterations in lid
opacities, decreased dark adaptation, keratitis, margins. Increased Staphylococcus aureus in
increased tear osmolarity, photophobia and conjunctival flora has also been reported.109,110
teratogenic ocular abnormalities. Decreased color Ocular adverse effects associated with other
vision is a reversible adverse effect. Few cases of vitamins are presented in Table 21.10.
Table 21.8 Ocular adverse effects of anticancer drugs

Busulphan Chronic myeloid leukemia Anterior subcapsular cataract
Docetaxel, paclitaxel Breast cancer Open-angle glaucoma
Methotrexate Psoriasis, Conjunctival hyperemia, photophobia, blepharitis,
rheumatoid arthritis periorbital edema, ocular irritation
Table 21.9 Ocular adverse effects of drugs used in dermatological disorders

Etretinate Cystic acne, severe refractive psoriasis Blepharoconjunctivitis
Isotretinoin Acne, psoriasis Cataract, night blindness, retinal toxicity, optic
neuritis, dry eye, blepharoconjunctivitis, keratitis,
corneal neovascularization, myopia
Table 21.10 Ocular adverse effects of vitamins

Vitamin A Acne, psoriasis Loss of brows and lashes, ocular palsies,
nystagmus, exophthalmos, papilledema, retinal
hemorrhage
Retinoic acid Xerophthalmia, acne, psoriasis Dry eye, corneal infection
Vitamin D Rickets, osteomalacia Band shaped corneal degeneration
Paricalcitol Secondary hyperparathyroidism Redness or discharge, increased light sensitivity
associated chronic renal failure
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Index
Page numbers followed by f refer to figure and t refer to table.
A Amino acids 279

cysteine 279
Abacavir 314 taurine 279
Abducent nerve 24 Aminoglycosides
Acanthamoeba 68, 259t, 268, 269 administration 127
ACE inhibitors 310 adverse effects 127
bacterial resistance 126
Acetazolamide 316
classification 125
Acetylcholine 210, 256
contraindications 128
Acinetobacter species 111, 126, 131
dosage 127
Active transport 30f, 36
therapeutic uses 127
Acute angle-closure glaucoma 250 Amiodarone 310
Acute conjunctivitis 111 Amitriptyline 307
Acute retinal necrosis 140, 141 Amlodipine 310
Adenoviruses 136, 138, 143 Amorolfine 153
Adenylyl cyclase-camp system 52 Amphetamine 306
Adverse drug reactions 63 Amphotericin B 146, 149, 151, 313-314
expected Ampicillin 314
secondary effects 63 Anidulafungin 152
side-effects 63 Annulus of zinn 15
toxicity 63 Antiallergic drugs 182-192
unexpected antihistamines 184-188
carcinogenicity 64 mast cell stabilizers 188
genetically determined 63 Anti-angiogenic agents 235
idiosyncratic reactions 64 aflibercept 235
immunologically mediated 63 bevacizumab 235
teratogenicity 64 ranibizumab 235
Anti-glaucoma drugs
Age-related macular degeneration 234
adverse effects, systemic 213
laser photocoagulation in 234
carbachol 211, 213
nutritional agents in
adverse effects 213
lutein 235 contraindications 213
zeaxanthin 235 therapeutic uses 213
photodynamic therapy in 234 ecothiophate 211, 213
verteporfin (visudyne) 234 adverse effects 213
Agonists 50, 51 contraindications 213
Alendronate 311 pilocarpine 211, 212
Allergic conjunctivitis 187 adverse effects 212
Allopurinol 312 ocular adverse effects 212
Alprazolam 307 Antihistamines 184-188
Amblyopia 91 Anti-inflammatory therapy, in dry eyes 240
Antioxidants 72 Betamethasone 178
Antiviral drugs 135-145, 136f Bifonazole 150
Aquaporins 10 Bioadhesive hydrogels 77
Aqueous enhancement therapy, in dry eyes 240 Bioavailability enhancer excipients 68
Aqueous humor 13f, 23 BK virus 136
Aqueous solutions 74 Blastomyces dermatitidis 147, 150
Artery Blepharitis 111
central retinal 16 Blepharocolysis 2
ciliary 16 Blepharospasm 2
dorsal nasal 16 Blood ocular barriers 37
ethmoidal 16
blood-aqueous 37
lacrimal 16
blood-retinal barriers (BRB) 37
maxillary 16
Bordetella pertussis 123
medial palpebral 16
Borrelia burgdorferi 121
meningeal 16
ophthalmic 3, 16 Borrelia recurrentis 121
supratrochlear 16 Botulinum toxin 256
Aspergillus niger 66 Buffers 242
Aspergillus species 147 Bullous keratopathy 250
Aspirin 312 Busulphan 315
Atopic keratoconjunctivitis (AKC) 207 Butenafine 153
Atorvastatin 311 Butoconazole 150
Atropine 90, 92
Augmentin 108 C
Autologous serum 243
Azathioprine 205 C. pneumoniae 122
C. psittaci 122
B Canal of Schlemm 11, 13
Candida spp. 66, 147-152, 154, 268
B. quintana 123 albicans 66, 268
Bacillus anthracis 106, 120 Canis 153
Bacitracin Carbachol 256
administration and dosage 130 Carbamazepine 308
contraindications of 131 Carbapenems 111
in blepharitis 131 adverse effects of 112
in chronic conjunctivitis 131
in bacterial endophthalmitis 112
in corneal ulcers 131
in prophylaxis of post-operative
in keratitis 131
endophthalmitis 112
mechanism of action of 130
Bacterial keratitis 111 Carrier-mediated transport 29
Bacteroides active transport 29
fragillis 111 facilitated diffusion 29
species 108, 121 Caspofungin 152
Bartonella henselae 123 Centrimonium 67
Beclomethasone 312 Cephalosporins 109,110t, 314
Behçet’s disease 205 First generation 109
Benzalkonium chloride (BAK) 66 Fourth generation 110
Benzatropine 306 Second generation 110
Beta lactam antibiotics 103 Third generation 110
Beta-blockers 306 Cevimeline 244
Index 323
Chlamydia spp. 113, 122 Copper 272
pneumoniae 116 deficiency 272
trachomatis 122 Corneal epithelial defects 199
Chlorambucil 205 Corneal herpetic lesions 139
Chloramphenicol 112, 314 Corneal hydrops 250
adverse effects 114 Corneal permeability coefficient 32
antibacterial spectrum 113 Corneal ulceration 111
in corneal ulceration 114 Corneal ulcers 91, 131, 151
in dacryoadenitis 114 Corticosteroids
in gonococcal conjunctivitis 114 adverse effects 176
in gonococcal corneal ulcer 114 anti-inflammatory effect 174
mechanism of action 112 classification 172
Chlorhexidine 68 contraindications 177
Chloroquine 314 immunosuppression effect 174
Chlorpheniramine 313 intraocular use 176
Cholinergic receptors 211, 211t periocular use 175
muscarinic 211 systemic use of 176
nicotinic 211 therapeutic uses of 174
Cholinomimetic drugs 211 topical use of 175
Chondroitin sulfate 242 Corynebacterium diphtheria 106, 121, 122
Choroidal neovascularization 295 Cotton pledgets 85
Ciliary body 13f Cryptococcus neoformans 147
Ciliary ganglion 17, 24 Crystallin proteins 14
Clobetasone butyrate (0.1%) 179 Crystalline lens 14
Clonazepam 307 Cyanocobalamin (vitamin B12) 278
Clostridia tetani 121 Cyclopentolate 92
Clostridium Cyclophosphamide 205
difficile 111, 122 Cycloplegia 90-91
perfringens 110 Cyclosporin A 243
tetani 106 Cyclosporine 205, 316
Clotrimazole 150 adverse effects 207
Coccidioides species 147 formulations 206
Codeine 307 mechanism of action 206f
Conjunctiva 2, 32 therapeutic uses 207
bulbar 32 Cytomegalovirus 136, 138, 139, 142, 143, 144
forniceal 32 infections 141, 142
palpebral 32 retinitis 142, 143, 144
Conjunctival hyperemia 199
Contact lenses 85, 265
cleaning systems 265
D
disinfection systems Dacryoadenitis 111
hydrogen peroxide 268 Dacryocystitis 111
multipurpose disinfecting solutions 268 D-alanyl-D-alanine 106
disinfection systems of 266 Demecarium 306
enzymatic cleaners for 266 Dendritic herpetic ulcer 140
rewetting solutions for 269 Dendric ulcer 138
storage case for 269 Desferoxamine 316
surfactant cleaners for 266 Dexamethasone 177, 312
soft hydrogel 265 Dexmethylphenidate 307, 316
soft silicone hydrogel 265 Dextrothyroxine 311
Diabetic retinopathy 25, 230f retrobulbar 24
drugs used 232t subconjunctival 22
anti-VEGF drugs 231 sub-tenon’s 23
bevacizumab 233 systemic 25
corticosteroids 233 topical 21
dexamethasone 233 Drug affinity 50
fluocinolone acetonide 234 Drug effects measurement
pegaptanib 231 graded dose-response curve 56
ranibizumab 231 quantal dose-response curve 57
triamcinolone acetonide 233 Drug safety measurement 58
vitreolytic agent 234 Drug-drug interactions 63
mild NPDR 229 Dry eyes 240
moderate NPDR 229 hormonal therapy in 240, 244
non-proliferative 229 syndrome 207
proliferative (PDR) 229 treatment 240, 244
severe NPDR 229
Diazepam 308
Didanosine 314
E
Difluprednate 0.05% 179 Echothiophate 306
Digoxin 310 Econazole 150
Diltiazem 310 Endocytosis 30
Diphenhydramine 313 Endophthalmitis 262
Diphenoxylate 316 Enfuvirtide 314
Diuretics 310 Enterobacter species 108, 110, 112, 126, 129
Docetaxel 315 Epidermophyton floccosum 153
Dornase alfa 316 Epithelial keratitis 140
Dosage forms 74, 77t Epstien barr virus 136, 139,142-144
Doxazosin 310
Erythromycin 314
Drug absorption 30, 38
Escherichia coli 66, 107, 108, 112,113,
ocular 37
126, 129, 131
systemic route 36
Estradiol 311
oral 36
Estrogen 311
parenteral 36
Ethambutol 314
topical route 30
transconjunctival 32 Ethanol 308
transcorneal 30 Ethinylestradiol 311
transscleral 33 Ethosuximide 308
Drug action Ethylene glycol dimethacrylate (EGDMA) 206
chemical reactions 55 Etretinate 315
inducing antibody formation 56 Excimer laser keratectomy 140
non-receptor mediated mechanisms 55 Extraocular irrigation 84
physical 56 Eyeball injuries 5
protoplasmic poisons 56 Eyelid edema 199
targeting enzymes 56
Drug administration routes F
intraocular 25
intracameral 25 Facilitated diffusion 29f
intravitreal 25 Fas ligands 16
periocular 22 Felbamate 308
peribulbar 24 Fenticonazole 150
Index 325
Fluoroquinolones 103, 115- 119, 314
adverse effects 118t
H
contraindications 119 H. influenzae 108
in acute bacterial conjunctivitis 117 H1 receptor blockers 184
in bacterial endophthalmitis 118 adverse effects of 186t
in bacterial keratitis 117 pharmacological effects 185
in blepharitis 117 anticholinergic effects 185
in gonococcal corneal ulcer 117 antiemetic effects 185
in prophylaxis for post-operative antiparkinsonian effects 185
endophthalmitis 118 sedation 185
interactions 119 topical ocular use 187
Fluorometholone acetate 178 antazoline phosphate (0.5%) 187
Fluvastatin 311 pheniramine maleate (0.3 %) 187
Folic acid (vitamin B9) 278 pyrilamine maleate (0.1%) 187
Fuch’s endothelial dystrophy 250 mast cell stabilizing combinations 190, 190t
Fusarium solani 268 H2 receptor blockers 184t
Haemophilus influenzae 107, 108, 110, 121, 123,
126, 129
G Hashish 308
Hepatitis B virus (HBV) 136
Gabapentin 308 infections 136
Gels 76 Helicobacter pylori 107, 121, 123
Gene therapy applications 292t Hemolytic streptococcus 109
in corneal alkali burn 294 Hepatitis 262
in corneal dystrophies 294 Heroin 308
in corneal graft rejection 292 Herpes simplex
in corneal neovascularization 293 keratitis 137
in corneal scarring and wound healing 293 keratoconjunctivitis 138
in glaucoma 295 Herpes viruses 144
Herpes zoster 140, 141
in ocular surface disorders 294
Histamine 182
Genital herpes infection 141
effects of 184t
Gentamicin 314 Histoplasma capsulatum 147, 150
Glands Homatropine 91
accessory glands of krause 3 Horner’s syndrome 2, 89
accessory lacrimal 3 HSV 136, 141, 135
lacrimal 3 HSV-1 137-139, 141-144
meibomian 1, 245 HSV-2 137-139, 141, 143
Glaucoma 14, 248, 249 Human immunodeficiency virus (HIV) 263
Glucocorticoids 190 Human recombinant interferon 205
Gold 312 Hyaluronidase 256
Gonococcal conjunctivitis 111 Hydralazine 310
Gonococcal corneal ulceration 111 Hydrocortisone 312
Hydroxyamphetamine 90, 306
Gonococcus 109
Hydroxyl ethyl methacrylate (HEMA) 206
Gramicidin 132 Hydroxypropyl methylcellulose (HPMC) 255
Granulomatosis 205 Hyoscine 91
Growth factors 256 Hypermetropia 9
epidermal growth factor (EGF) 256 Hyperosmotic agents 246t, 247, 247f
fibroblast growth factor (FGF) 257 glycerol (glycerin) 248
transforming growth factors (TGFs) 257 isosorbide 249
Gypseum153 mannitol 248
topical 250 Laser-assisted in-situ keratomileusis (LASIK) 140
glycerol (glycerin) 250 Lasik surgery 89
hypertonic saline 250 Leber’s congenital amaurosis (LCA) 295
Hyphema 199 Leptospira species 121, 106
Hypopyon 199 Leuprolide 316
Levator palpebrae muscle 1
I Levetiracetam 308
Levonorgestrel 311
Ibuprofen 312 Levothyroxine 311
Indomethacin 312 Lid scrubs 84
Infective waste disposal 263 Linezolid 314
Infraorbital fissure 5 Lipid emulsion 243
Infraorbital foramen 6 Lipophilic drugs 31, 32
Infraorbital sulcus 5 Listeria 111
Insulin 311 Listeria species 106, 121, 122
Interdigitalis 153 Lithium 308
Interferons 208 Local anesthetic
adverse effects 209
adverse effects 199
mechanism of action 209
local 199
Inverse agonists 51
on cardiovascular system 199
Ionotropic receptors (type I receptors) 52f
on central nervous system 199
Iopamidol 316
contraindications 200
Iritis 139, 140
injectables 196t
Isocarboxazid 308
Isoniazid 314 local infiltration 201
Isosorbide 310 mechanism of action 197
Isotretinoin 315 peribulbar block 201
retrobulbar block 200
sub-tenon’s block 201
K topical 195t, 201
Local anterior uveitis 199
Keratitis 140, 131, 151
Keratoconjunctivitis 240 Losartan 310
treatment approach 240 Loteprednol etabonate 178, 190
Ketorolac 190 Lovastatin 311
Ketotifen 190 LSD 308
Klebsiella species 108,112, 126, 129, 131 Lutein 275
Lycopene 274f
L
M
Lacrimal
fossa 5 M. scrofulaceum 122
gland 3, 240, 245 Macrolides
papilla 3 adverse effects 124t
sac 3 contraindications of 124
Lactamase inhibitor combinations 109 in bacterial conjunctivitis 123
Lactoferrin 4 in blephritis 123
Lamivudin 314 in chronic or recurrent conjunctivitis 123
Lamotrigine 308 in trachoma 124
L-ascorbate. See L-ascorbic acid interactions of 124
L-ascorbic acid 278 mechanism of action of 122
Index 327
Magnesium 272 Muscles
deficiency 272 dilator pupillae 12
Manganese 273 extraocular 15, 15f, 24
deficiency 273 inferior oblique 1, 6, 15, 16
Marijuana 308 inferior rectus 6,15
Mast cell stabilizers 188 lateral rectus 6, 15
adverse effects 189 medial rectus 6, 6f, 15
cromolyn 188 levator palpebrae superioris 1, 2, 16
disodium chromoglycate (cromolyn) 188 superior oblique 15,6
lodoxamide (0.1%) 189 superior rectus 15,6
mechanism of action 188 muller’s/superior tarsal 2
nedocromil sodium (2%) 189 orbicularis oculi 1, 2
sphincter pupillae 12
ocular use 189
superior tarsal 2
pemirolast (0.1%) 189
Mycobacterium spp. 117
Measurement drug effects measurement 56
Mycobacterium kansasii 122
Medroxyprogesterone 311
Mycophenolate mofetil 205
Meibomian gland, dysfunction 2
Mycoplasma 113, 121
Mescaline 308 Mydriatics, Contradictions 88t
Metabotropic receptors 53f Mydriatics, indications 88t
Methadone 308 Myopia 9
Methotrexate 205, 315
Methyl dopa 310
Methyl phenidate 308 N
Methyl predinosolone 312
Naftifine 153
Methylphenidate 308 Nasolacrimal apparatus 3
Micafungin 152 Natamycin 147-149
Miconazole 150-151 Neisseria spp. 110,123, 130
Microsporum gonorrhoea 106, 108, 110, 120, 126
audouinii 153 meningitidis 106, 110, 126, 129
canis 153 Nerves
gypseum 153 abducent 17
Midazolam 307 frontal 6, 17
Mitomycin C 257 inferior ophthalmic 16
Modified drug responses 59 lacrimal 6, 17
acquired tolerance 60 maxillary 17
acute tolerance 60 nasociliary 6, 17
drug tolerance 59 oculomotor 2, 17, 24
natural tolerance 59 ophthalmic 16, 17
pharmacodynamic tolerance 60 optic 6, 12, 14, 17
pharmacokinetic tolerance 60 trigeminal 2, 10
Molluscum contagiosum 136 trochlear 17
Mometasone 312 zygomatic 17
Monobactams 112 Niacin 311
Morphine 308 Niacinamide (vitamin B3) 277
Mucoadhesives 69, 69t Nifedipine 310
Moraxella species 117 Nitrates 310
Muller’s muscle 2, 88-89 Nitroglycerine 310
paralysis of 2 Non-beta lactam antibiotics 112
Multiple dose administration and dosing schedule 46 in acute bacterial conjunctivitis 114
in blepharitis 114 metabolism 159
in bacterial keratitis 114 pharmacological actions 160
Non-steroidal anti-inflammatory analgesia 160
drugs (NSAIDs) 163 emesis 161
adverse effects 167 euphoria 160
mechanism of action 164t histamine release 161
pharmacological actions 165 miosis 161
analgesic 166 respiratory depression 160
anti-inflammatory action 166 sedation 160
antiplatelet action 166 suppression of cough reflex 161
therapeutic uses 166 receptor subtypes 158
analgesic 166 dynorphins 158t
anti-inflammatory 167 endorphin 158t
antiplatelet action 167 enkephalin 158t
antipyretic 167 therapeutic uses 161
Nonviral vectors acute pulmonary edema 162
nanoparticles 291 analgesia 161
hybrid metal-polymeric 291 cough suppression 162
metallic 291 diarrhea 162
polymeric 291 topical ocular use 163
NSAIDs, Topical ocular use 169t Opium 308
Nystatin 146-148 Orbit 4
apperture 6, 7t
O dimensions 5f
infection spread in 6
Ocular decongestants 190 malignancy spread in 6
adverse effects 191 margins 5
naphazoline 191 walls 5,6t
oxymetazoline 191 fractures 6
phenylephrine 191 inferior 6
tetrahydrozoline 191 lateral 6f
Ocular drug medial 6f
bioavailability 38 superior 6
distribution 39 Orbital apex syndrome 9
elimination 41 Orphenadrine 313
metabolism and elimination 41 Oxacephems 112
Ocular infection indications 109 Oxcarbazepine 308
Omega-3 fatty acids 240, 245 Oxiconazole 150
Omeprazole 313 Oxybutynin chloride 306
Opioid (narcotic) analgesics 157
absorption 159 P
adverse effects 162
classification 159t P. aeruginosa 110, 113, 116, 126
contraindications 162 Paclitaxel 315
head injury 162 Palpebral fissure 89
impaired hepatic functions 162 Pantothenic acid (vitamin B5) 277
impaired renal functions 162 Papillary hypertrophy 199
reduced pulmonary function 162 Parabens 67
distribution 159 Paricalcitol 316
mechanism of action 157 Parkinson’s disease 2, 271
Index 329
Partial agonists 51 Phenothiazines 308
Passive diffusion 28f, 31, 36 Phenylephrine 88-90
Pasteurella spp. 131 Phenylephrine (10%), usage guidelines 90t
Penciclovir 140-141 Phenytoin 308
Penetration enhancers 70 Phospholipase C-inositol phosphate system 53
Penicillin-binding protein (PBP) 106 Physostigmine 91
Penicillins Pilocarpine, contraindications 213
aminopenicillins 107 Pimecrolimus 208
antipseudomonal penicillins 108 Pinguecula 3
beta lactamase inhibitor combinations 108 Pirenzepine 313
natural penicillins 106 Pneumococcus 109, 117
ophthalmic use 108 Polyangiitis 205
penicillin G 106 Polyhexamethylenebiguanide 68
penicillin V 106 Polymeric gels 77
penicillinase-resistant penicillins 107 Polymyxin B
Peptococcus 121 adverse effects 132
Phagocytosis 3 in blepharitis 132
Pharmacodynamics 50-64 in blepharoconjunctivitis 132
Pharmacokinetics 28-47 in conjunctivitis 132
acyclovir 314, 139-140 in corneal ulcers 132
aminoglycosides 125,126 in keratitis 132
anesthetics, 195, 196, 197 mechanism of action 131
azoles 150, 150t Polyquaternium-1 67
bacitracin 130, 131 Post-herpetic neuralgia 140
chloramphenicol 113 Post-operative endophthalmitis 262
cidofovir 142,143 Pralidoxime 306
corticosteroids 172, 244 Pravastatin 311
cotrimoxazole 129 Prazosin 306
disodium chromoglycate 188 Prednisolone
echinocandins 152 acetate 177
famciclovir 140-141 sodium phosphate 177
flucytosine 148-149, 154 Prednisone 312
foscarnet 143-144 Preservatives 65, 66t
ganciclovir 141,142 Primidone 308
griseofulvin 153 Progestogens 311
H1 receptor antagonists 185 Propionibacterium 121
hyperosmotic, 247, 247f Proteus spp. 110, 126
idoxuridine (IDU) 137 mirabilis 107
macrolides 122, 123 Pseudomonal keratitis 111
nanoparticle 296 Pseudomonas spp. 110, 111, 116
NSAIDs 164 aeruginosa 66, 108, 112, 117, 126, 127, 131, 268
opioids 159 Psilocybin 308
polyenes 146, 147, 147t Pterygium 3
polymyxin B 131 Pterygopalatine ganglion 3
terbinafine 154 Ptosis 2, 89
tetracyclines 121 Pupillary light reflex 19f
trifluridine 137 direct 18
vidarabine 138 indirect 18
Phenobarbitone 308 Pyridoxine (vitamin B6) 277
Q Scleral spur 11
Scleritis 12
Quinidine 310 Scopolamine 91, 306
Quinine 314 Secretagogues 240, 244
Quinolones and fluoroquinolones 116t Selective serotonin 308
first generation 116 Selenium 273
fourth generation 116
Serratia spp. 126
in gonococcal conjunctivitis 117
mechanism of action 116 marcescens 268
second generation 116 Sertaconazole 150
third generation 116 Shigella species 107, 113,129, 131
Sildenafil 316
R Simvastatin 311
Sirolimus 205, 208
Ranitidine 313 Sjogren’s syndrome 244, 274
Receptors 52 Smallpox 136
actions 55
Sodium hyaluronic acid 255
desensitization 55
down-regulation 55 Sodium perborate 68
spare receptors 55 Solifenacin succinate 306
supersensitivity 55 Sorbic acid 67
upregulation 55 Spirochetes 120
cytoplasmic receptors 54 Sporothrix schenckii 147
enzyme-linked receptors 54 SSRIS 308
Retina 14
Stabilized oxychloro complex (SOC) 68
Retinal vein occlusion 235
anti-platelet therapy 236 Staphylococci 117
drugs used 236 Staphylococcus spp. 106, 108, 111,113, 122, 130
hydroxyethyl starch or dextran 236 aureus 66, 108, 129, 268
ticlopidine 236 pyogenes 109
troxerutin 236 Sterilization methods 258
Retinitis 140, 142-143 Streptococcus species 106,111, 120, 130
Retinitis pigmentosa (RP) 295
pneumoniae 129
Retinoic acid 316
Reuptake inhibitors 308 pyogenes 129
Riboflavin (vitamin B2) 276 viridans 129
Rickettsiae species 113, 120, 121,123 Stromal keratitis 140
Rifabutin 314, 316 Subconjunctival
Rimexolone 178 hemorrhage 24
Rofecoxib 312 injections 111
Rosuvastatin 311
Sulconazole 150
Sulfonamides 128, 314
s administration and dosage 129
adverse effects 129
S. aureus 107, 108
S. pneumoniae 116 local 129
Salbutamol 306 systemic 130
Salmonella species 113, 107, 131 classification 128
Sclera 11, 33 contraindications, 130
episclera 33 cotrimoxazole 129
lamina fusca 33 mechanism of action 128
stroma 33 trimethoprim (TMP) 128
Index 331
Sulfonylureas 311 mentagrophytes 153
Surfactants 71 rubrum 153
Suspensions 74 schoenleini 153
Systemic drug 89 sulphureum 153
elimination half-life 43 tonsurans 153
excretion 42 verrucosum 153
first order kinetics 43 Trochlear fossa 5
metabolism and excretion 41 Tropicamide 93
mixed order kinetics 45
zero-order kinetics 44
U
T Unasyn 108
Ureaplasma 121
Tacrolimus 205, 207 urealyticum 122
Tadalafil 316 Uveitis 91
Tamoxifen 311
Tamsulosin 306
Tarsal meibomian glands 3 V
Tear film 2, 3, 240
Vaccinia 138, 143
Tenon’s capsule 11f
Valacyclovir 139, 140
Terazosin 310
Valdecoxib 312, 312
Tetracyclines 120, 121, 244, 314
Valganciclovir 141-142
adverse effects 121
Valproic acid 308
bacterial resistance of 121
Vardenafil 316
blepharitis 121
Varicella species 139
classification 120, 120t
in acute conjunctivitis 121 Varicella zoster virus (VZV) 135, 141-142
in bacterial endophthalmitis 121 Vehicles 68
in bacterial keratitis 121 Vein
in corneal ulceration 121 inferior ophthalmic 6, 16
in dacryoadenitis 121 infraorbital 16
in ophthalmia neonatorum 121 superior ophthalmic 3, 6
mechanism of action 120 Venlafaxine 308
TGF-B2 16 Verapamil 310
Thiabendazole 149 Vernal conjunctivitis 189
Thiamine 276 Vibrio cholera 121
Thimerosal 67 Vigabatrin 308
Tiagabine 308 Viral vectors 287, 288f
Ticarcillin disodium 108 adeno-associated virus (AAV) 288, 289, 295
Timentin 108 recombinant 289
Tioconazole 150 self-complementary 289
Tolterodinet artrate 306t adenovirus (AV) 287, 295
Topiramate 308 lentivirus 290, 295
Toxic anterior segment syndrome (TASS) 25 retrovirus 290
Trachoma 121 Viscosity enhancers 68
Treponema pallidum 106, 121, 123 Visual pathway 18f
Trichophyton Vitamin A 274, 316
crateriform 153 Vitamin B 276
gallinae 153 Vitamin C 278
interdigitalis 153 Vitamin D 275, 316
megnini 153 Vitamin E 276
Vitreous humor 14
Voclosporin 208
Z
VZV 19, 138, 139, 141-143 Zeazanthin 275
Zidovudine 314
Zinc 271
W deficiency 271
toxicity 272
Warfarin 315 Zoster ophthalmicus 139

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Textbook on

Clinical Ocular Pharmacology

Renu Agarwal PhD

Sushma Srivastava PhD

The Health Sciences Publishers

Jaypee Medical Inc Jaypee Brothers Medical Publishers (P) Ltd

Jaypee Brothers Medical Publishers (P) Ltd

© 2014, Jaypee Brothers Medical Publishers

Textbook on Clinical Ocular Pharmacology and Therapeutics

Brinnell Annette Caszo PhD Preeti Sankaran MD

ANTI-HISTAMINICS, DECONGESTANTS, ASTRINGENT

Oxymetazoline Sympathomimetic Decongestant Visine LR Solution 0.025% Topical

Naphazoline Sympathomimetic Decongestant, Clear Eyes 0.0125% Topical

Prednisolone Glucocorticoid Anti- Ecocnopred Suspension 1% Topical

Rimexolone Glucocorticoid Anti-inflammatory Vexol Suspension Topical

Triamcinolone Glucocorticoid Anti-inflammatory Triesence 40 mg/mL Intraocular

Carteolol Beta-blocker Oculohypotensive Generic Solution 1% Topical

Mannitol Hyperosmotic agent Oculohypotensive Osmitrol Solution 5–20% Intravenous

Combination Trade name Formulation

Bacitracin/hydrocortisone/neomycin/ Generic Suspension,Ointment: 400 units—1%

Fluconazole Diflucan Oral: 150 mg single dose; 200 mg on day 1

Intravenous: 100–400 mg daily

Also used to treat

5. Ophthalmic Formulations and 10. Antifungal Drugs 146

11. Drugs Used in Ocular 18. Drugs Used in the Treatment of

Blood Supply, Lymphatic Drainage Eyelid movements occur in coordination with

Figure 1.3 Glands secreting the tear film

THE BONY ORBIT

Orbital Margins Table 1.1 Dimensions of the orbit7

Superiorly, the orbital margin is formed by the Depth 50–70 mm

Table 1.2 Walls of the orbit

Orbit Composing structures Relations

Aperture Location Boundaries Contents Surgical Importance

Inflammatory Infectious ** Neoplastic Traumatic/ Iatrogenic Vascular

Figure 1.9 Cornea

occurring. Aquaporins (AQP1) have also been Tenon’s Capsule

Figure 1.10 Tenon’s capsule

The Sclera pressure. Interspersed between the collagen fibrils

Figure 1.13 Extraocular muscles

Figure 1.14 Visual pathway

Figure 1.15 Pupillary and accommodation reflex pathways

overview eyelid is gently pulled away from the globe and

overview barriers. The major transport mechanisms that

Figure 3.4 Corneal epithelium

Figure 3.5 Corneal stroma and endothelium

Figure 3.7 Conjunctival epithelium

Flow chart 3.1 Fate of topically administered drugs

Figure 3.9 Apparent volume of distribution

Figure 3.11 Steady-state concentration is achieved in 4–5 t1/2

Table 3.1 First versus zero order kinetics

First order kinetics Zero-order kinetics

Figure 3.14 Steady-state achieved after loading and maintenance dose

OVERVIEW of drug with receptors is usually specific and

Figure 4.1 Drug-receptor interactions

Types of Receptors (GPCR). GPCR consist of seven transmembrane

Figure 4.4 G-protein linked metabotropic receptor activation

Figure 4.5 Second messenger system activation by G-proteins

Figure 4.6 Transmembrane signaling by tyrosine kinase linked receptors

resistant. Helicobacter pylori

Adverse Effects 6. Bacterial endophthalmitis: Usually combin

Gram-positive bacilli (Bacilus anthracis,

3. Azithromycin and clarithromycin have improved pharmacokinetic properties—better bioavailability, better

4. Clarithromycin and azithromycin have advantages over erythromycin in dosing regimen.

5. The Gram-positive activity of clarithromycin is superior to that of erythromycin and azithromycin.

6. Azithromycin offers increased Gram-negative coverage compared to erythromycin and clarithromycin.